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Delayed Enucleation of Eyes with Advanced Intraocular Retinoblastoma Due
to Pre-enucleation Treatment Increases Metastatic Death
Junyang Zhao, MD1, Meirong Wei, MD2, Guohua Liu, MD3, Zhao Xun Feng, BSc4, Carlos E.
Solarte5 MD, FRCSC, Bin Li, MD6, Yizhuo Wang, MD7, Chengyue Zhang, MD1, Brenda L.
Gallie, MD, FRCSC4, 8-9
Authors’ affiliations
1 Department of Ophthalmology, Beijing Children’s Hospital, Capital Medical University,
National Center for Children’s Health, China.
2 Department of Ophthalmology, LiuZhou Maternal and Child Health Care Hospital, China.
3 Department of Ophthalmology, Qilu Children’s Hospital of Shan Dong University, China.
4 Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto,
Ontario, Canada.
5 Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta,
Canada.
6 Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, China
7 Department of Pediatric, Beijing Tongren Hospital, Capital Medical University, China.
8 Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine, University
of Toronto, Toronto, Ontario, Canada.
9 Division of Visual Sciences, Toronto Western Research Institute, Toronto, Ontario, Canada.
Corresponding author: Junyang Zhao, 56 Nanlishi Lu, Xicheng District, Beijing, China,
100045 [email protected]
Running Head: Delayed Enucleation of Advanced Retinoblastoma Increases Death
Word count: /3000 words
1
Numbers of figures and tables: 1 consort diagram, 3 figures and 3 tables and 3 online only
figures
Key Words: retinoblastoma, enucleation, chemotherapy, pathology
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Purpose
Advanced intraocular retinoblastoma can be cured by primary enucleation. With
recent advances in treatment modalities, there is a trend toward trial salvage
which can delay enucleation. We hypothesized that delayed enucleation over a
defined length of time would increase metastatic death.
Patients and Methods
Histopathology and disease-specific survival A multicenter retrospective review ofwere
analyzed for 554 eyes/spatients) primarily and or secondarily enucleated for
GroupGroups D and E retinoblastoma (IIRC).. One eye enrolled per child. Treatment
groups were compared for histopathology and disease-specific survival.
Results
Primarily enucleated eyes had median ≤ 0.1 month from diagnosis to enucleation.
In comparison, pre-enucleation chemotherapy delayed enucleation (groupGroup
D: median 8.4 months; groupGroup E: median 2.8 months). Disease-specific
survival was lower with prolonged delay between diagnosis and enucleation.
Delay > 3.5 months (groupGroup D) and > 2 months (groupGroup E) were
associated with diminished survival (groupGroup D: p = .02; groupGroup E: p
= .02). Fewer eEyes treated with pre-enucleation chemotherapy had fewer high-
risk histopathology (pT3/pT4) than primarily enucleated eyes (groupGroup D: p
= .04; groupGroup E: p = .003). Children with groupGroup E eyes and 1 to 3 cycles
of pre-enucleation chemotherapy had no difference in survival as than children
those primarily enucleatedwith primary enucleation, but those withthose with ≥ 4 cycles
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A B S T R A C T
had lower survival than primarily enucleated children primarily enucleated (p = .03).
Children with high-risk eyes (pT3/pT4) after pre-enucleation chemotherapy had
diminished survival than compared to primarily enucleated children with high-risk
eyes primarily enucleated (p = .002).
Conclusion
We showed that there is a window of opportunity in which enucleation is most
effective and no amount of pre-enucleation chemotherapy did not confer any
survival benefit. Timely enucleation, < 3.5 months (groupGroup D) and < 2 months
(groupGroup E), minimizeds the risk of metastatic death.
4
Retinoblastoma is the most common primary malignant intraocular tumor of the eye.1 It accounts
for 4% of all pediatric malignancies affecting one in every 16,000 to 18,000 live births.2-4 If
discovered early, retinoblastoma is one of the most treatable curable cancers. The International
Intraocular Retinoblastoma Classification (IIRC) (2005) staged tumor eyes from GroupGroup A
(very low riskhigh chance to salvage eye safely) through E (very low high chance to salvage eye
and risk to liferisk) to predict outcome following systemic chemotherapy and consolidation focal
therapy.5 IIRC predicts ≥ 90% chemotherapy success for eye salvage of groupGroups A, B and
C eyes.6 Even advanced retinoblastoma (groupGroups D and E) confined to the eye can be cured
by simple enucleation. However, of concern is that delayed enucleation may increase risk of
extraocular tumor extension which that has limited curative options for cure and high mortality
rate.7,8
Unlike other pediatric cancers, rigorous controlled clinical trials in retinoblastoma is are
missing few for a multitude ofmany reasons, including: low incidence prevalence of disease to
interest pharmaceutical industry,, complexity with of bilateral disease, and vision preservation as
an outcome measure competing outcome measure towith cure of cancer.1 Therefore, Multi-
center collaboration in research is essential important to advance evidence for clinical
management of retinoblastoma. This study reviewedWe now report on 600 children enucleated
for advanced (Groups D and E) retinoblastoma, expanding on and is an expansion of our 2011
publication in 2011 which identified a that delay > 3 months from diagnosis to enucleation
increaseds mortality for children with groupGroup E eyes.8 Since thenNow, there has been an
increasing shift toward salvage of more groupGroup D eyes are salvaged by use ofwith vision-
preserving combinations of systemic chemotherapy,9 and lately intravitreal chemotherapy,10-12
5
I N T R O D U C T I O N
intra-arterial chemotherapy (IAC),13-15 periocular chemotherapy,16 and tumor endoresection via
pars plana vitrectomy.17 Trial eye salvage with any of these modalities can delays enucleation.
Our aim is toWe now re-evaluate the risk to life of delayed enucleation for both groupGroups D
and E eyes. Our sSecondary objective is to measure to study the relationship betweenimpact of
pre-enucleation systemic chemotherapy and on histopathologic features indicating risk for
extraocular disease and their effect on long-term patient survival.
Data Collection and Ethics
This was a retrospective study of all IIRC groupGroups D and E eyes in children who
hadtreated with primary and secondary enucleation at 29 Chinese treatment centers between
January 17, 2006 and December 26, 2010. The final follow-up date accounted in this study was
December 13, 2017. Clinical information collected included age at diagnosis, sex, disease
laterality (unilateral/bilateral), IIRC5 clinical staging of diseased eyes at diagnosis, and age at
diagnosis, date of enucleation, neoadjuvant and adjuvant treatments, last follow-up date,
evidence of extraocular extension and date of death. IIRC (2005) staging5 determined at
diagnosis were was retrospective recordedused at time of data collection and retrospective
review of data did not permit conversion to the current newer cTNMH staging by the( 8th Edition
American Joint Committee on Cancer, (AJCC).18 The study was approved by the ethics boards
of Beijing Children’s Hospital, Beijing Tongren Hospital, Liuzhou Maternal and Child Health
Care Hospital and Qilu Children’s Hospital of Shan Dong University in accordance with the
Declaration of Helsinki.
Eligibility
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M E T H O D S
Of 600 children, none had clinical evidence of extraocular disease or metastasis at diagnosis
by lumbar puncture, bone marrow aspiration, computed tomography and/or magnetic resonance
imaging. For analysis of effect of delayed enucleation on mortality, excluded were children who
died from chemotherapy toxicity and children with bilateral advanced retinoblastoma (D/D, D/E,
E/D or E/E). For analysis of effect of pre-enucleation chemotherapy (cycles or presence/absence)
on mortality, in addition to the above exclusion criteria, children with less than one complete
chemotherapy cycle (< 3 weeks) or those with salvage therapy other than systemic chemotherapy
were secondarily excluded (Figure 1).
Histopathologic Assessment
All enucleated eyes were initially pathologically staged initially using the 7th Edition AJCC
pTNM19 based on review of hematoxylin and eosin-stained slides. Microscopic slides included
multiple section levels of the mid-globe, both calottes and surgical margin of optic nerve.
Evaluated features included the presence and extent of tumor invasion into the optic nerve,
anterior chamber, choroid and sclera. A second independent reviewer updated the histopathology
staging to 8th Ed. AJCC pTNM18 (Table 1) via by review of pathology reports and representative
microscopic sections. For analysis, histopathologic risk was condensed into two groupGroups:
low-risk (pT1 and pT2) and high-risk (pT3 and pT4). High-risk features include massive
choroidal invasion (≥ 3 mm), scleral invasion, episcleral invasion, retrolaminar optic nerve
invasion and invasion of optic nerve surgical margin. Table 1 summarizes the 8th Ed. AJCC
pathological staging.
Statistical Analysis
Sex, age at diagnosis, time from diagnosis to enucleation, follow-up since diagnosis,
systemic chemotherapy or not before enucleation, histopathologic risk (high vs low risk),
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systemic chemotherapy or not after enucleation and IIRC eye classification staging (groupGroup
D or E) were summarized using frequency/percentage for categorical variables and median/range
for continuous variables. Baseline characteristics of children with and without pre-enucleation
chemotherapy were compared using Pearson’s chi-squared test for categorical variables and
Mann-Whitney U test for continuous variables. Receiver-operating characteristic (ROC) analysis
was used to determine true positive rate (TPR) and false positive rate (FPR) for all possible cut
off values of time from diagnosis to enucleation in relation to disease-specific survival (DSS)
(Supplement 1). For any given threshold, TPR is the proportion of dead children correctly
predicted, while FPR is the proportion of living children wrongly predicted to be dead. The
thresholds with the highest TPR were identified, among from which the one with the lowest FPR
was selected. TPR was prioritized in threshold selection given the greater importance of correctly
identifying children at risk of metastasis. Thresholds were used for to placeing children into
categorical groupGroups for survival analysis. Kaplan-Meiier (KM) survival analysis was
associated to log-rank test for to testing survival equality. Cox proportional-Hazards model was
used additionally to calculate survival equality and hazard ratio between sub-groupGroups.
Length of DSS was measured from date age of diagnosis to date age of metastatic death. Patients
alive were censored at last follow up. All P-values reported are two sided and less than 0.05
indicated significance. All analysis was performed using STATA version 15.1 (Stata
Corporation) and SPSS Version 25 (IBM Corp).
Patient Clinical Information
A total of 202 groupGroup D and 352 groupGroup E eyes from 554 children (335 males,
and 219 females) were included, with a median age of 23 months (range, 1 to 122 months) at
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R E S U L T S
diagnosis. Non-studied eyes of bilaterally affected children were IIRC groupGroup A (in 27
)cases, groupGroup B (in 32) cases and groupGroup C (in 20) cases. Enucleation was the
primary treatment for 275 eyes, while and 279 eyes were treated initially with systemic
chemotherapy prior to enucleation (Table 2). In addition to systemic chemotherapy, 29 children
also received Other other salvage treatments in addition to systemic chemotherapy: IAC (in 18)
cases, PPV endoresection (in 6) cases, plaque radiotherapy (in 3) cases, 1 case of stem cell
transplantation (1) and 1 case of immunotherapy (1). Sex and age at diagnosis were not
significantly different between children with and without pre-enucleation systemic
chemotherapy. The medium Time from diagnosis to enucleation were was median ≤ 0.1 months
for primarily enucleated groupGroups D and E eyes. In comparison, pre-enucleation
chemotherapy significantly delayed enucleation (groupGroup D median 0.1 vs 8.4 months, P
< .001; groupGroup E median 0-day vs 2.8 months, P < .001). GroupGroup E eyes with pre-
enucleation chemotherapy had longer follow-up than groupGroup E eyes primarily enucleated
(median 93 vs 84 months, P = .03). Higher proportion of primarily enucleated eyes had high-risk
histopathology (pT3 and pT4) than eyes treated with chemotherapy (groupGroup D 21% vs 11%,
P = .04; groupGroup E 34% vs 20%, P = .003). Fewer children with pre-enucleation
chemotherapy than primarily enucleated children received post-enucleation chemotherapy
(groupGroup D, 14% vs 51%, P < .001; groupGroup E, 47% vs 62%, P = .03).
Pre-enucleation Chemotherapy
Median pre-enucleation chemotherapy cycles were was 4 (range, 1 to 15 cycles). The
chemotherapy regimens used were carboplatin, etoposide/teniposide, and vincristine. Eyes were
removed when tumors progressed with no possibility of useful vision.
Patients Died from Retinoblastoma Metastasis
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Of 22 children who died from metastasis, 6 had groupGroup D and 16 had groupGroup E
eyes; , among which 14 had received pre-enucleation chemotherapy (median, 5.5 cycles) and 11
had received post-enucleation chemotherapy (median, 3 cycles) (Table 3). The median time
from diagnosis to enucleation was 3.7 months (range, 0 to 42.3 months). Histopathologic
examination identified 5 eyes as low-risk and 17 eyes as high-risk. pTNM staging were: 4 pT1
[18%], 1 pT2b [5%], 2 pT3a [9%], 4 pT3b [18%], 2 pT3c [9%] and 9 pT4 [41%].
Primary Outcomes
ROC analysis identified time from diagnosis to enucleation > 3.5 months (groupGroup D)
and > 2 months (groupGroup E) as cut offs (Supplement 2 and 3). For survival analysis,
groupGroup D eyes were placed into two groupGroups: eyes enucleated < 3.5 months and > 3.5
months from time of diagnosis. GroupGroup E eyes were groupGrouped into eyes enucleated < 2
months and > 2 months from time of diagnosis (Figure 2).
An association of delayed enucleation with diminished survival was identified. Survival was
lower if enucleation of groupGroup D eyes were delayed > 3.5 months from diagnosis (48-month
DSS, 93% vs 100%; P = .02). No child with groupGroup D eye enucleated within 3.5 months
died. For children with groupGroup E eyes, survival was lower if enucleation were delayed > 2
months (48-month DSS 97% vs 90%; HR = 3.10; P = .02).
Secondary Outcomes
After secondary exclusion, 510 eyes (177 groupGroup D and 333 groupGroup E) were
studied for the effect of pre-enucleation chemotherapy cycles on survival (Figure 3).
GroupGroup E eyes that received 1 to 3 cycles of systemic chemotherapy had no difference in
survival as primarily enucleated eyes (48-month DSS, 97% vs 96%; Hazard ratio = 0.77; P =
.74). However, those with four or more cycles of chemotherapy had diminished survival (48-
10
month DSS, 86% vs 96%; HR = 3.35; P = .03). For children with groupGroup D eyes, 4 with
pre-enucleation chemotherapy died, while all primarily enucleated children survived. However,
the number is too few for survival analysis.
Of enucleated eyes with low histopathologic risk (pT1 and pT2), children with pre-
enucleation chemotherapy or not had no difference in survival (48-month DSS, 99% vs 99%;
Hazard ratio = 0.94; P = .95; Figure 4). Despite similar adverse histopathology (primary vs
secondary enucleation % pT4, 15% vs 25%, P = .255), high-risk eyes that received systemic
chemotherapy had lower survival than high-risk eyes primarily enucleated (48-month DSS, 59%
vs 93%; HR = 5.05; P = .002).
Exploratory Outcomes
Of 554 children studied, 248 received systemic chemotherapy after enucleation, with a
median of 3 cycles (range, 1 to 15 cycles; Supplement 4). Of 440 low-risk children (pT1 and
pT2), 150 received post-enucleation chemotherapy and 16 of 114 high-risk children (pT3 and
pT4) did not receive post-enucleation chemotherapy. Low-risk children with and without post-
enucleation chemotherapy had no difference in survival (48-month DSS, 99% vs 99%; Hazard
ratio = 0.49; P = 0.52). High-risk children with post-enucleation chemotherapy had better
survival than high-risk children without post-enucleation chemotherapy (48-month DSS, 89% vs
49%; Hazard ratio = 0.21; P < 0.001).
Although advanced intraocular retinoblastoma is relatively rare in developed countries, it is the
most common presentation in the developing world. In low to mid-income Asian countries,
groupGroups D and E disease constitutes 78% to 89% of all intraocular retinoblastoma cases.20,21
Multi-center collaboration enabled us to accrue the largest dataset of enucleated groupGroups D
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D I S C U S S I O N
and E eyes. Family and physician may choose to use pre-enucleation systemic chemotherapy for
various reasons including the desire for eye salvage, parental resistance to enucleation and the
belief that chemotherapy would lower risk of metastasis.
Particularly relevant today because of shifting emphasis toward salvage therapy, our study
highlights the risk to life with prolong delay to enucleation. We showed that delayed enucleation
from diagnosis > 3.5 months for groupGroup D eyes and > 2 months for groupGroup E eyes
increase risk of metastasis. Given reported salvage rate of 47% to 95% for groupGroup D eyes
from centers worldwide,15,22 trial salvage of groupGroup D eyes during the first 3.5 months after
diagnosis may be justified. GroupGroup E eyes usually present with irreversible ocular damage
and high probability of adverse histopathology;23-26 immediate enucleation is the safest option.
Retinoblastoma team can take advantage of the 2-month grace period to counsel parents who are
resistant to enucleation of groupGroup E eyes.
The AJCC pTNM staging classifies the risk of metastasis based on extent of tumor invasion
and guides post-enucleation treatment. But, despite having the same advanced histopathology
staging (pT3 and pT4), children who received pre-enucleation chemotherapy had diminished
survival compare to primarily enucleated children. High-risk histopathology after pre-
enucleation chemotherapy may be an indicator that the tumor is chemotherapy-resistant.
Therefore, treatment with the same regimen of chemotherapy (VEC) post-enucleation may be
ineffective at clearing off resistant microscopic metastasis. Our study underscores the important
of not solely relying on pTNM staging for post-enucleation management especially when pre-
enucleation chemotherapy was used.
In this study, children with pre-enucleation chemotherapy had fewer adverse histopathology
but no improved survival compared to primarily enucleated children. This confirms hypothesis
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from our previous publication that pre-enucleation chemotherapy masks histopathologic risk.8
The fewer high-risk histopathology also explains the finding of fewer children with pre-
enucleation chemotherapy than primarily enucleated children received post-enucleation
chemotherapy.
Our study also confirmed finding by others that post-enucleation chemotherapy should be
reserved to children with high-risk histopathology.27-29 For children with low-risk eyes, post-
enucleation chemotherapy exposes them to toxicity without any survival benefit. In this study,
two children died from chemotherapy toxicity. They both had post-enucleation chemotherapy
despite pT1 and pT2b histopathology. Post-enucleation chemotherapy may have been given to
low-risk children out of fear of masked high-risk features. Our study now demonstrates that
chemotherapy to low-risk children does not improve survival. Five children died from tumor
metastasis despite low-risk histopathology. These eyes all had focal choroidal invasion or
pre-/intra-laminar invasion but not both. The worse survival of these children compared to
children with neither of these features prompts further study into the risk profile of
histopathologic features. Another possibility is that adverse features were present in these eyes
but weren’t in the studied sections.
In summary, our study confirmed the danger of delayed enucleation in children with
advanced intraocular retinoblastoma. We showed that no amount of pre-enucleation systemic
chemotherapy confers any survival benefit. Instead, delay to enucleation > 3.5 months
(groupGroup D) and > 2 months (groupGroup E) from systemic chemotherapy increases risk of
death from metastasis. Primary enucleation remains the method that best achieves cure while
prolong eye salvage risks life of the child.
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A U T H O R S ’ D I S C L O S U R E
O F C O N F L I C T S O F
The author(s) indicated no potential conflicts of interest.
Conception and design: Junyang Zhao, Meirong Wei, Guohua Liu, Zhao Xun Feng, Carlos E.
Solarte, Brenda L. Gallie
Administrative support: Bin Li
Provision of study materials or patients: Junyang Zhao, Meirong Wei, Guohua Liu
Collection and assembly of data: Junyang Zhao, Meirong Wei, Guohua Liu, Zhao Xun Feng,
Yizhuo Wang, Chengyue Zhang, Brenda L. Gallie
Data analysis and interpretation: Junyang Zhao, Zhao Xun Feng, Carlos E. Solarte, Brenda L.
Gallie
Manuscript writing: All authors
Final approval of manuscript: All authors
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A U T H O R
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