preenucleation chemoterapy

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Pre-Enucleation Chemotherapy for Eyes Severely Affectedby Retinoblastoma Masks Risk of Tumor Extension andIncreases Death From MetastasisJunyang Zhao, Helen Dimaras, Christine Massey, Xiaolin Xu, Dongsheng Huang, Bin Li, Helen S.L. Chan,and Brenda L. Gallie

From the Beijing Tongren Eye Centre,

Beijing Tongren Hospital, Capital Medi-

cal University, Beijing, China; The

Hospital for Sick Children; Campbell

Family Institute for Cancer Research,

Ontario Cancer Institute/Princess

Margaret Hospital, University Health

Network; and the University of Toronto,

Toronto, Ontario, Canada.

Submitted September 7, 2010;

accepted December 10, 2010;

published online ahead of print at

www.jco.org on January 31, 2011.

Supported by the Ontario Ministry of

Health and Long Term Care

(OMOHLTC); the Kalmar Family Trust

for the One Retinoblastoma World

Network; and the Canadian Retinoblas-

toma Society. The views expressed do

not necessarily reflect those of the

OMOHLTC.

Authors disclosures of potential con-

flicts of interest and author contribu-

tions are found at the end of thisarticle.

Corresponding author: Brenda L. Gallie,

MD, FRCSC, Campbell Family Cancer

Research Institute, Ontario Cancer Insti-

tute/Princess Margaret Hospital, Univer-

sity Health Network, University of

Toronto, 610 University Ave, Toronto,

Ontario, Canada M5G 2M9; e-mail:

[email protected].

2011 by American Society of Clinical

Oncology

0732-183X/11/2907-845/$20.00

DOI: 10.1200/JCO.2010.32.5332

A B S T R A C T

PurposeInitial response of intraocular retinoblastoma to chemotherapy has encouraged primary chemo-therapy instead of primary enucleation for eyes with clinical features suggesting high risk ofextraocular extension or metastasis. Upfront enucleation of such high-risk eyes allows pathologicevaluation of extraocular extension, key to management with appropriate surveillance and

adjuvant therapy. Does chemotherapy before enucleation mask histologic features of extraocularextension, potentially endangering the childs life by subsequent undertreatment?

MethodsWe performed retrospective analysis of 100 eyes with advanced retinoblastoma enucleated with,or without, primary chemotherapy, in Beijing Tongren Hospital, retrospectively, from October 31,2008. The extent of retinoblastoma invasion into optic nerve, uvea, and anterior chamber onhistopathology was staged by pTNM classification. The treatment groups were compared forpathologic stage (Cochran-Armitage trend test) and disease-specific mortality (competingrisks methods).

ResultsChildren who received chemotherapy before enucleation had lower pTNM stage than primarilyenucleated children (P .01). Five patients who received pre-enucleation chemotherapy died asa result of extension into brain or metastasis. No patients who had primary enucleation died. For

children with group E eyes, disease-specific survival (DSS) was lower with pre-enucleationchemotherapy (n 45) than with primary enucleation (n 37;P .01). Enucleation longer than3 months after diagnosis was also associated with lower DSS (P .001).

ConclusionChemotherapy before enucleation of group E eyes with advanced retinoblastoma downstagedpathologic evidence of extraocular extension, and increased the risk of metastatic death fromreduced surveillance and inappropriate management of high-risk disease, if enucleation wasperformed longer than 3 months after diagnosis.

J Clin Oncol 29:845-851. 2011 by American Society of Clinical Oncology

INTRODUCTION

Metastasisof retinoblastomais rarein thedevelopedworld, where early diagnosis achieves cure for most

children.1 Cure of retinoblastoma outside the eye is

rare. Metastatic retinoblastoma in treated with sys-

temic and intrathecal/intraventricular chemothera-

py, stem-cell transplantation, and in some cases

radiation, with some success.2-8

Retinoblastoma confined to the eye can be

cured by simple enucleation, and usually no further

treatment is necessary. The enucleated eye is studied

for histopathologic evidence of tumor invasion to

evaluate risk of tumor spreadoutside theeye, classi-

fied by the American Joint Committee on Cancer

(AJCC) pTNM classification.9 Patients displaying

unfavorable pathology may be treated with adju-vant chemotherapy and/or active surveillance to

identify extraocular retinoblastoma when cure is

still feasible.10

Intraocular retinoblastoma groups A to D, In-

ternational Intraocular Retinoblastoma Classifica-

tion (IIRC),11 can initially respond dramatically to

chemotherapy. This has resulted in a trend to also

usechemotherapy for more severely affected eyes in

IIRC group E, which exhibit clinicalsigns associated

with highriskfor extraocular disease. Thisapproach

is often attributed to parental reluctance to remove

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

V OL UM E 2 9 N UM BE R 7 M A RC H 1 2 01 1

2011 by American Society of Clinical Oncology 845

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the childs eye, or the expectation that chemotherapy might make the

surgicalremovalof the eyesafer. However, chemotherapymaydown-stage pathologic features associated with risk for extraocular exten-

sion, which otherwise would suggest adjuvant therapy and/or

surveillance. This could result in undertreatment and lossof opportu-

nity for cure.We performed a retrospective case study of 100 enucleated IIRC

group D and E eyes that were either primarily enucleated or treated

with prior primary chemotherapy, to determine the effect of pre-

enucleation chemotherapy on the histologic detection of risk for ex-traocular extension and patient outcome.

METHODS

Data Collection and EthicsAll data were collected retrospectively with approval from the Capital

MedicalUniversity, Beijing TongrenHospitalEthics Board. Datawas analyzedwith approval of the research ethics board of the University Health Network,Toronto, Canada.Anonymized clinical datawere recorded includingsex,date

of birth, age at diagnosis, disease laterality (unilateral/bilateral), IIRC group atdiagnosis, family history of retinoblastoma, follow-up duration, chemothera-py regimen, evidence of extraocular extension, and date of death.

Inclusion and Exclusion CriteriaPatients were selected based on the IIRC group of their enucleated eye

confirmed at the initial staging examination under anesthesia, and date ofenucleation.The100IIRC groupD orE eyes enucleatedat theBeijingTongrenHospital, Beijing, China, between May 19, 2006, and October 31, 2008, wereincludedin this study.The eyes were enucleated eitheras primary treatmentorafter chemotherapy.

No patient hadclinical evidence of metastasisat presentationby lum-bar puncture (LP), bone marrow aspiration, and MRI and/or computedtomography. Approximately 24 to 48 hours before each chemotherapycycle, examination under anesthesia, and prechemotherapy cryotherapy

(single freeze-thawto oneor twospotsin peripheral retina) were performedtoenhance chemotherapy penetration into the eye.12 Children were excludedfrom this study if there wasevidenceof clinical metastasis at presentation, or ifthey had been treated with chemotherapy plus focal laser and/or therapeutictriple freeze-thaw cryotherapy, since this indicates more extensive effort tosave the eye than simple pre-enucleation chemotherapy.

Histologic AssessmentThe extent of tumor in optic nerve, choroid and anterior chamber were

scored based on the written histopathology reports and confirmed by retro-spective rereview of hematoxylin and eosinstained slides. The AJCC pTNM9

stage was for each eyewas based on extent of tumor invasion into optic nerve,choroid, and/or anterior chamber. Evidence of metastasis was collected fromMRI,computedtomography,LP, and/or bonemarrow aspiration reports.Forsomeanalyses, childrenwere grouped intolow (pT1), moderate(pT2),or high

(pT3, pT4) risk for metastasis (Table 1).

Statistical AnalysisDisease-specific survival (DSS) was measured from date of diagnosis to

date of death from disease in the study eye. Death not due to disease or notfrom thestudy eyewastreatedas a competing risk.Patientsalive were censoredat lastfollow-up.Univariable analysesof DSSwereconductedusing Grays testand plots of 1 minus the cumulative incidence function. Other univariableanalyses were conducted using Fishers exact test, the Wilcoxon rank sumtest, and the Cochran-Armitage trend test, and allPvalues reported for thesetestsare exact Pvalues.Pvaluesreported forall tests were twosided. There wasno missing data. Competing risks analyses13 were performed usingthe cmprskpackage in R 2.10.1 (http://www.r-project.org/). All other analysis was gener-ated using SAS version 9.2 (SAS Institute, Cary, NC).

RESULTS

Patients

Histopathology reports of 100 enucleated retinoblastoma eyes

from 100 children (61 male, 39 female; 28 bilateral, 72 unilateral; 18

group D, 82 group E) were retrospectively staged for pTNM staging

features. Re-examination of histopathology by a second reviewer(B.L.G.) showed 100% concurrence with low-, moderate-, and high-

risk staging (Table 1).

Enucleation was the primary treatment for 45 eyes. Chemo-

therapy was the primary treatment for 55 eyes enucleated without

other treatments. The two groups showed no significant differ-

ences between sex, unilateral versus bilateral, IIRC group of the

eye(s), or age at diagnosis (Table 2). The bilaterally affected child

who died due to disease was diagnosed at age 24 months (overall

median age bilateral diagnosis 15 months; range, 4 to 77); the

unilaterally affected children who died were diagnosed at ages 9,

35, and 37 months (overall median age unilateral diagnosis 27

months; range, 4 to 77). Median follow-up was longer for patientsalive at last follow-up treated with primary enucleation (median,

31.2 months; minimum/maximum 10.3 to 44.9) than with pre-

enucleation chemotherapy (median, 25 months; minimum/maxi-

mum 11.5 to 38.4; Table 2).

Only one of 28 bilateral patients (patient 33) had bilateral group

E disease (Table 2, Fig 1). The study eye was removed at diagnosis.

After enucleation, five cycles of chemotherapy were given, but the

child was lost to follow-up 19 months after initial diagnosis, so there is

no furtheroutcome for theretained group E eye or current status. The

remaining patients had groups A to D disease in the remaining eyes

(Fig 1). Each patient contributed only one eye to this study.

Table 1. pTNM Risk for Metastasis

Risk and pTNM Definition

Low

pTX Primary tumor cannot be assessed

pT0 No evidence of primary tumor

pT1 Tumor confined to eye with no optic nerve orchoroidal invasion

Moderate

pT2a Tumor superficially invades optic nerve he adbut does not extend past lamina cribrosa

pT2a Tumor exhibits focal choroidal invasion

pT2b Tumor superficially invades optic nerve he adbut does not extend past lamina cribrosaand exhibits focal choroidal invasion

High

pT3a Tumor invades optic nerve past laminacribrosa but not to surgical resection line

pT3a Tumor exhibits massive choroidal invasion

pT3b Tumor invades optic nerve past laminacribrosa but not to surgical resection lineand exhibits massive choroidal invasion

pT4a Tumor invades optic nerve to resection linebut no extra-ocular extension identified

pT4b Tumor invades optic nerve to resection lineand extra-ocular extension identified

Zhao et al

846 2011 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY



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Pre-Enucleation Chemotherapy

Pre-enucleation chemotherapy every 3 to 4 weeks consisted of

one to 12 cycles (median, 3 cycles) of carboplatin, etoposide, and

vincristine/carboplatin, teniposide, and vincristine, with cyclosporine

doses lower than therapeutic doses previously published.14,15 Eyeswere removed when the tumors progressed with no possibility of

useful vision.

Time From Diagnosis to Enucleation

Median time from diagnosis to enucleation was 0.1 months

for primarily enucleated eyes, and 3 months for eyes that received

pre-enucleation chemotherapy (P .001; Table 2). Group E eyesthat received pre-enucleation chemotherapy were removed sooner

(median, 2.8 months) than group D eyes (median, 8.6 months),

indicating the poor response of group E eyes to therapeutic inter-vention (Table 2).

Primary Outcomes

Five children died of metastasis. No children whohad primary

enucleation (Figs 1, 2), and no child with a group D eye in the

study, died of tumor. For group E eyes in the chemotherapy group,

four children (8.9%) died due to disease in the study eye by lastfollow-up. For all children who died, the time from diagnosis until

enucleation was longer than 3 months. In the no chemotherapy

group, none of the patients died due to disease by last follow-up,

one patient (2.7%)experienceda competingrisk (died from chem-

otherapy complications).

Patient 22 presented with leukocoria and bilateral groups E/D

retinoblastoma at age 21 months. The group E eye was removed after

2.5 months after seven cycles of chemotherapy. No adverse features

were present on pathology (pT1). Four more cycles of chemotherapy

were given forthegroup D eye. The opticnerve was foundenlarged 1.5

years after diagnosis, further treatment was refused,andthe child died

Table 2. Features of Children and Enucleated Eyes

Parameter


P

No Yes

No. % No. %

Sex

FemaleMale

17 38 22 40 .84

28 62 33 60

Group worst eye

DE

8 18 10 18 1.00

37 82 45 82

Laterality

UnilateralBilateral

33 73 39 71 .83

12 27 16 29

No. % MedianMinimum to

Maximum No. % MedianMinimum to

Maximum

Age at diagnosis, months

D

Unilateral 6 13 31 8-37 6 11 23 9-36

Bilateral 2 4 6 4-9 4 7 10 3-16

Total 8 18 27 4-37 10 18 19 3-36

E

Unilateral 27 60 27 4-77 33 60 27 2-122

Bilateral 10 22 15 1-41 12 22 21 2-41

Total 37 82 26 1-77 45 82 25 2-122

All patients 45 26 1-77 55 23 2-122 .92

Unilateral patients 33 28 4-77 39 27 2-122 .73

Bilateral patients 12 13 1-41 16 19 3-41 .37

Diagnosis to enucleation, months

D

Unilateral 6 13 0.3 0-12 6 11 9 2-14

Bilateral 2 4 0.5 0-1 4 7 6 0.8-13

Total 8 18 0.3 0-12 10 18 9 0.8-14

E

Unilateral 27 60 0.1 0-12 33 60 3 0.2-19

Bilateral 10 22 0.4 0-3 12 22 4 0.9-18

Total 37 82 0.1 0-12 45 82 3 0.2-19All patients 45 0.1 0-12 55 3 0.2-19 .001

Follow up, months 44 31 10-45 50 25 12-38

Fishers exact test.Wilcoxon rank sum test.Follow-up for patients alive at last follow-up.

Increased Mortality From Retinoblastoma

www.jco.org 2011 by American Society of Clinical Oncology 847



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pre-enucleationchemotherapy would tendto be longerthanforthose

without, simply because they had to live through longer diagnosis-

until-enucleation periods to be included in the study. Despite this

built-in bias, theDSSwassignificantlylower forchildrenwith group E

eyes who received chemotherapy before enucleation than for those

whodidnot (Fig 2A; 24 month DSS was 95% and100%, respectively,

Grays testP .01), or if enucleation was delayed by longer than 3

months (Fig 2B; 24 month DSS was 90% and 100%, respectively,Grays test P .001).

In the longer than 3 months group, four patients (16.7%) died

due to disease by last follow-up, and one patient died from disease

from the other eye (competing risk). The remaining patients were

censored. In the0- to 3-monthgroup, none of thepatients died due to

disease by lastfollow-up,one patient (1.7%) experienceda competing

risk and the remaining 57 patients (98.3%) were censored at last

follow-up. Themedian time forDSS cannotbe estimated forthe 0- to

3-month group since there has not been enough follow-up for their

cumulative incidence function to reach 0.50. The estimated median

DSS for the longer than 3 month group is 30.6 months.

Similarly, the number of cycles of chemo for all pre-enucleation

chemotherapygroup E patientssignificantly affectedDSS,comparingoutcome for those who received more than four cycles to those who

received 4 cycles (Grays test P .01). The median time to disease-

specific death in the more than four cycles group was 30.6 months.

Histologic Risk Factors of Metastasis

Overall, pre-enucleation chemotherapy was associated with

lower risk staging (P .01) with thepTNM stage collapsed into low-,

moderate-, andhigh-risk groups (Table 1).Thiswas significant forthe

D eyes (P .02), but a similar trend for E eyes was not statistically

significant (P .09; Table 3). Patient 68 diedof intracranial extension

of unilateral retinoblastoma, yet the enucleated eyeshowed a risklevel

of pT2a, which would not suggest adjuvant treatment. For the pre-enucleation chemotherapy group, pTNM risk (low/moderate/high)

was negatively correlated with time between diagnosis and enucle-

ation(Spearmanrankcorrelation coefficient0.30;95%CI,0.47

to0.11; P .002).

Post-Enucleation Chemotherapy

Seventy-fourpercent(74of 100) of patients receivedchemother-

apy (median four cycles; minimum, one cycle; maximum, 12 cycles)

after enucleation (Fig1). Thepostenucleation chemotherapyregimen

was the same as the pre-enucleation chemotherapy regimen. Overall,

treatment with postenucleation chemotherapy correlated to degree

(low/moderate/high) of histologic risk (P .02), however, the num-

ber of cycles given was not consistent for the pTNM the risk groups.

Fifty-two percent (13 of 25) of children with low-risk pathology and

81.3% (48 of 59) with moderate-risk pathology received postenucle-

ation chemotherapy, although no published data suggests that low or

moderate-risk justifiesadjuvant therapy.16 Nineteen percent (three of

16) of children with high-risk pathology did not receive postenucle-

ation chemotherapy, which conventionally might be clinically indi-

cated.16 Univariable tests did not suggest that the decision to give

postenucleation chemotherapy was associated with laterality or

IIRC group.

DISCUSSION

Next to India, China has the most new patients with retinoblas-

toma.1,17 Accrual of such a large a cohort of enucleated eyes in a short

period of time (100 eyes in 2.5 years) is nearly impossible in other

countries, due to the low incidence of retinoblastoma.1,17

We understand that a combination of desire to save the eye

andvision,parentalrefusal of recommendedenucleation,andtheidea

that treatment might make removal of the eye safer was rationale

for pre-enucleation chemotherapy. However, we show that pre-

enucleationchemotherapymaskedunfavorablepathology thatwould

warrant further therapy and/or surveillance, and gave the illusion of

tumor response while extraocular disease progressed to death.

The AJCC pTNM staging is designed to assess the risk of

tumor dissemination and guide further treatment for the child. Inthis study, the postenucleation chemotherapy regimen was not

consistent with the pTNM risk (Fig 1). For bilateral patients, the

chemotherapy might have been given to treat the other eye, but

unilaterally affected children with no histopathologic risk factors

also received postenucleation chemotherapy.

Wespeculatethatifthefourchildrenwhodiedofmetastasisfrom

their study eye had undergone immediate enucleation, the cancer

mighthave notyet extended outside theeye, or if high-risk pathologic

risk factors had been recognized, postenucleation surveillance and

adjuvant therapy might have avoided metastatic deaths. The pre-

enucleation chemotherapy given in this study poorly treated tumors

already outside the eye, and failed prevent extension outside the eye.

High-risk optic nerve invasion was not treated with orbital radiother-apy although thismight conventionally havebeenconsidered in addi-

tion to the postenucleation chemotherapy.

Delay of treatment is commonly known to contribute to poor

outcomes.18 In addition, the pre-enucleation chemotherapy masked

thetrue extent of extraocularextension,andmayhave renderedposte-

nucleation chemotherapy ineffective by promoting multidrug resis-

tance.19 One patient died despite low-risk pathology (patient 68,

pT2a) in the enucleated eye, suggesting that high-risk clinical and

pathology features that led to death might have been obscured by the

pre-enucleation chemotherapy. We also observed pathologic down-

staging of group D eyes treated with pre-enucleation chemotherapy.

Table 3. Pre-Enucleation Chemotherapy and Risk of Metastasis by pTNM

pTNM Risk forMetastasis


P

No Yes

No. % No. %

All eyes

High 9 20 7 13

Moderate 31 69 28 51

None 5 11 20 36 .01

Group D

High 1 12 0 0

Moderate 7 88 5 50

None 0 0 5 50 .02

Group E

High 8 22 7 16

Moderate 24 65 23 51

None 5 14 15 33 .09





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Shorter follow-up times for children who received pre-enucleation chemotherapy suggests an increasing clinical practice

trend to administerpre-enucleation chemotherapy. Weshowthat this

trend carries a severe risk to the life for children with retinoblastoma.In comparison, primary enucleation of even group E eyes is curative.

The fewer group D than E eyes enucleated in the study time

periodreflects that some group D eyes canbe saved,consistent withtheir less severe involvement. Success to salvage group D eyes

ranges from 30% to 50% at retinoblastoma treatment cen-

ters worldwide.19

In this treatment center, approximately 99% of group E eyes

were not saved by chemotherapy. If a group E eye was not enucle-

ated, it was because parents refused treatment and did not returnfor follow-up, and these children likely died. Several published

papers that claim cure of group E eyes, actually report eyes that are

incorrectly downstaged to be group D eyes.20,21 Our data recon-firms the urgency to primarily enucleate group E eyes.11,22 Perhaps

only when clinical trials show cure of 70% of group D eyes and

early-detected extraocular retinoblastoma, should we attempt tosave group E eyes.

Most children whose enucleation was delayed because of chem-otherapy did not develop metastasis. Formal studies are necessary tostudy the overall impact of chemotherapy and repeated examinations

under anesthesia on families and children. Particularly, any immedi-

ate and future systemic adverse effects and risks and financial costs tofamily and health resources must be weighed against the remote pos-

sibility of successful treatment of severely involved eyes. One child

whohadnot received pre-enucleationchemotherapydied fromposte-nucleation chemotherapy toxicity.

Unlike in other pediatric cancers, no significant clinical trials as

yet support the care of children with retinoblastoma.23 Starting in the1950s, radiation therapy for intraocular retinoblastoma swept the

world after dramatic responses in intraocular tumors.24 No clinical

trial evaluated the long-term outcomes of radiation. Only 20 years

later was it noticed that more people had died of radiation-inducedsecondary cancers than of retinoblastoma.25 Chemotherapy replaced

primary radiation in the 1990s,19 again with dramatic responses in

intraocular retinoblastoma, but again, no multicenter clinical trialshavesystematically evaluated negative outcomes, suchas theincreased

mortality we now document retrospectively. Another dramatic ther-

apy, intra-arterial chemotherapy, swept the world for all stages ofintraocular retinoblastoma, including group E eyes.26 The data we

report here raise the alarming potential that children with group E

tumorstreatedwith intra-arterial chemotherapyface an increased riskof death from metastasis, when simple enucleation of the eye would

have saved their life with minimal morbidity for unilaterally af-

fected children.Also alarming is the possibility thattheremainder of the children

on this study is not out of danger, since with a longer follow-up more

children may ultimately die of metastases.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design:Junyang Zhao, Helen Dimaras, Helen SL Chan,Brenda L. GallieAdministrative support:Bin LiProvision of study materials or patients: Junyang ZhaoCollection and assembly of data: Junyang Zhao, Helen Dimaras, XiaolinXu, Dongsheng Huang, Bin Li, Brenda L. GallieData analysis and interpretation:Junyang Zhao, Helen Dimaras,Christine Massey, Helen SL Chan, Brenda L. GallieManuscript writing:All authors

Final approval of manuscript:All authors

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