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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
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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.
Methods
A multicenter retrospective review of 554 eyes primarily and secondarily enucleated for groups
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 (group D: median 8.4 months; group E:
median 2.8 months). Disease-specific survival was lower with prolonged delay between
diagnosis and enucleation. Delay > 3.5 months (group D) and > 2 months (group E) were
associated with diminished survival (group D: p = .02; group E: p = .02). Eyes treated with pre-
enucleation chemotherapy had fewer high-risk histopathology (pT3/pT4) than primarily
enucleated eyes (group D: p = .04; group E: p = .003). Children with group E eyes and 1 to 3
cycles of pre-enucleation chemotherapy had no difference in survival as children with primary
enucleation, but those with ≥ 4 cycles had lower survival than children primarily enucleated (p
= .03). Children with high-risk eyes (pT3/pT4) after pre-enucleation chemotherapy had
diminished survival than children with high-risk eyes primarily enucleated (p = .002).
Conclusion
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A B S T R A C T
We showed that there is a window of opportunity in which enucleation is most effective and no
amount of pre-enucleation chemotherapy confer any survival benefit. Timely enucleation, < 3.5
months (group D) and < 2 months (group E), minimizes the risk of metastatic death.
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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 cancer. The International Intraocular
Retinoblastoma Classification (IIRC) (2005) staged tumor from group A (very low risk) through
E (very high risk) to predict outcome following systemic chemotherapy and consolidation focal
therapy.5 IIRC predicts ≥ 90% chemotherapy success for salvage of groups A, B and C eyes.6
Even advanced retinoblastoma (groups 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 has limited curative options and high mortality rate.7,8
Unlike other pediatric cancers, rigorous controlled clinical trial in retinoblastoma is missing
for a multitude of reasons including: low incidence of disease to interest pharmaceutical industry,
complexity with bilateral disease and vision preservation as a competing outcome measure to
cure of cancer.1 Therefore, multi-center collaboration in research is essential to advance evidence
for clinical management of retinoblastoma. This study reviewed 600 children enucleated for
advanced retinoblastoma and is an expansion of our publication in 2011 which identified a delay
> 3 months from diagnosis to enucleation increases mortality for children with group E eyes.8
Since then, there has been an increasing shift toward salvage of group D eyes by use of systemic
chemotherapy9 and lately intravitreal chemotherapy,10-12 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 delay enucleation. Our aim is to re-evaluate the risk of
delayed enucleation for both groups D and E eyes. Secondary objective is to study the
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INTRODUCTION
relationship between pre-enucleation systemic chemotherapy and histopathologic risk and their
effect on long-term patient survival.
Data Collection and Ethics
This was a retrospective study of all IIRC groups D and E children who had 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 include age at diagnosis, sex, disease laterality (unilateral/bilateral),
clinical staging of diseased eyes at diagnosis, date of enucleation, neoadjuvant and adjuvant
treatments, last follow-up date, evidence of extraocular extension and date of death. IIRC (2005)
staging5 were used at time of data collection and retrospective review of data did not permit
conversion to the newer cTNM 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
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 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
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METHODS
chemotherapy cycle (< 3 weeks) or those with salvage therapy other than systemic chemotherapy
were secondarily excluded (Figure 1).
Histopathologic Assessment
All enucleated eyes were 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 via review of pathology reports and representative microscopic
sections. For analysis, histopathologic risk was condensed into two groups: 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),
systemic chemotherapy or not after enucleation and IIRC classification (group 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)
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(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 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 placing children into
categorical groups for survival analysis. Kaplan-Mier (KM) survival analysis was associated to
log-rank test for testing survival equality. Cox proportional-Hazards model was used
additionally to calculate survival equality and hazard ratio between sub-groups. Length of DSS
was measured from date of diagnosis to date 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 group D and 352 group 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 diagnosis.
Non-studied eyes of bilateral children were IIRC group A in 27 cases, group B in 32 cases and
group C in 20 cases. Enucleation was the primary treatment for 275 eyes, while 279 eyes were
treated initially with systemic chemotherapy prior to enucleation (Table 2). 29 children also
received 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 and 1
case of immunotherapy. Sex and age at diagnosis were not significantly different between
children with and without pre-enucleation systemic chemotherapy. The medium time from
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RESULTS
diagnosis to enucleation were ≤ 0.1 months for primarily enucleated groups D and E eyes. In
comparison, pre-enucleation chemotherapy significantly delayed enucleation (group D median
0.1 vs 8.4 months, P < .001; group E median 0-day vs 2.8 months, P < .001). Group E eyes with
pre-enucleation chemotherapy had longer follow-up than group 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 (group D 21% vs 11%, P
= .04; group E 34% vs 20%, P = .003). Fewer children with pre-enucleation chemotherapy than
primarily enucleated children received post-enucleation chemotherapy (group D, 14% vs 51%, P
< .001; group E, 47% vs 62%, P = .03).
Pre-enucleation Chemotherapy
Median pre-enucleation chemotherapy cycles were 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
Of 22 children who died from metastasis 6 had group D and 16 had group E eyes, among
which 14 received pre-enucleation chemotherapy (median, 5.5 cycles) and 11 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 (group D) and > 2
months (group E) as cut offs (Supplement 2 and 3). For survival analysis, group D eyes were
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placed into two groups: eyes enucleated < 3.5 months and > 3.5 months from time of diagnosis.
Group E eyes were grouped 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 group D eyes were delayed > 3.5 months from diagnosis (48-month DSS,
93% vs 100%; P = .02). No child with group D eye enucleated within 3.5 months died. For
children with group 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 group D and 333 group E) were studied for the
effect of pre-enucleation chemotherapy cycles on survival (Figure 3). Group 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-month DSS, 86% vs 96%; HR = 3.35;
P = .03). For children with group 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
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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,
groups 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 groups D 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 group D eyes and > 2 months for group E eyes increase risk of
metastasis. Given reported salvage rate of 47% to 95% for group D eyes from centers
worldwide,15,22 trial salvage of group D eyes during the first 3.5 months after diagnosis may be
justified. Group 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
11
DISCUSSION
take advantage of the 2-month grace period to counsel parents who are resistant to enucleation of
group 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
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
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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 (group D)
and > 2 months (group 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.
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
13
AUTHORS’ DISCLOSURE OF CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
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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