-
- 赵军阳副主任医师
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医院:
首都医科大学附属北京儿童医院
科室:
眼科
- Global Issues and Opportunities for Optimized Retinoblastoma Care--2007 Pediatric Blood & Cancer
- 作者:赵军阳|发布时间:2013-06-20|浏览量:3852次
pediatr blood cancer 2007;49:1083?1090
brenda l. gallie, md,1* junyang zhao, md,2 kirk vandezande, phd,3
abigail white, bsc,4 and helen s.l. chan, md
5
introduction
retinoblastoma is a rare cancer of the eye that occurs in infancy
or early childhood [1] which presents dramatic contrasts.with early北京同仁医院眼肿瘤科赵军阳
diagnosis, retinoblastoma is easily cured. delayed diagnosis results
in visual impairment or blindness and risk of extraocular retinoblastoma
with faint hope of cure.
mortality of retinoblastoma in developed countries is about
4%, and deaths are more often from radiation-induced or sporadic
secondary malignancies than metastatic retinoblastoma. in stark
contrast, in less developed contexts, mortality may be as high as
90% because of both late diagnosis and lack of expert resources
focused on retinoblastoma.
the scientific approach to retinoblastoma also reveals stark
contrasts between the evident clarity of understanding of cancer
established through the study of retinoblastoma [2] and the failure,
for many reasons, to apply clinical science to development of
therapies for this disease [3]. the rb1 gene [4] is the first tumor
suppressor gene identified, and sparked an explosion of the study of
cell cycle control in cancer. the highest level of sensitivity in
molecular detection of rb1 mutations in individual retinoblastoma
families [5] has been achieved and the impact of this diagnostic
test, in conjunction with superior quality of care for retinoblastoma,
on the reduction of healthcare cost has been evaluated scientifically
[5][6]. by contrast, basic approaches to early diagnosis and effective
therapy are lacking in many emerging countries. randomized
controlled clinical trials and evidence-based medicine have very
effectively changed the outcomes of cancers in children in general,
but this has not been the case for retinoblastoma [3], in part
because insufficient patients have been available to power clinical
trials [7]. the many obstacles of how to apply clinical science to the
treatment of retinoblastoma might be solved by real global
collaboration.
basic causes of retinoblastoma
cancer susceptibility associated with rb1 mutation
the incidence of retinoblastoma is 1 in 15,000?20,000 live
births, regardless of sex, race, or geography [8]. most children are
diagnosed before 3 years of age. knudson conceived the ‘‘two-hit
hypothesis’’ by recognizing that hereditary retinoblastoma was
diagnosed at a younger age than unilateral non-familial retinoblastoma.
this theory suggested only two rate-limiting events in the
initiation of retinoblastoma: two somatic events in non-heritable
(always unilateral disease), or one somatic event after a first,
heritable event (usually bilateral disease) [9]. based on retinoblastoma,
the broad concept of tumor suppressor genes was conceived
[10], proven [2,11,12], and loss of heterozygosity was recognized to
be the major mechanism by which tumor suppressor genes initiate
cancer. rb1 [4] was cloned by first identifying a dna fragment at
chromosome 13q14 that was totally missing in one retinoblastoma
tumor [13]. the rb1 gene is relatively large and mutations can occur
anywhere in its 27 exons or the promoter region [5].
all retinoblastoma tumors are missing rb1 gene function, due to
mutations (m) of the first rb1 allele (m1) and then the second rb1
allele (m2) in the cell in the developing retina that ultimately forms a
tumor. of all the children with retinoblastoma, 60% developed a
tumor because both m1 and m2 occurred in one single retinal cell
that became their unilateral tumor, and their relatives are not at risk.
in 40% of children, the mutation in the first allele (m1) is carried in
constitutional cells, and may have been inherited from a parent, or
have arisen in a gamete before conception or in only a fraction of the
cells of the embryo resulting in mosaicism for the mutant rb1 allele
[14]. individuals with one constitutional mutant rb1 allele are
completely normal except for high cancer susceptibility. they
usually (90%) develop bilateral retinoblastoma, but may also
develop unilateral disease or no tumors.
rb1 gene function can be lost in many ways [5]: deletion of all or
part of the gene, its translocation onto another chromosome,
mutations that alter rna splicing, or point mutations leading to
truncation of translation or amino acid substitution. in tumors, but
not constitutional cells, methylation of the rb1 promoter can also
eliminate the function of the rb1 gene. the most frequent m2 event
is loss of heterozygosity, in which large regions containing the m1
mutant allele are reduplicated on the second allele. this is widely
the rb1 gene is important in all human cancers. studies of
human retinoblastoma point to a rare retinal cell with extreme
dependency on rb1 for initiation but not progression to full
malignancy. in developed countries, genetic testing within affected
families can predict children at high risk of retinoblastoma before
birth; chemotherapy with local therapy often saves eyes and vision;
and mortality is 4%. in less developed countries where 92% of
children with retinoblastoma are born, mortality reaches 90%.
global collaboration is building for the dramatic change in mortality
that awareness, simple expertise and therapies could achieve in less
developed countries. pediatr blood cancer 2007;49:1083?1090.
2007 wiley-liss, inc.
key words: retinoblastoma; suppressor genes
2007 wiley-liss, inc.
doi 10.1002/pbc.21350
??????
1retinoblastoma program, hospital for sick children and applied
molecular oncology, ontario cancer institute/princess margaret
hospital, university health network, university of toronto, toronto,
ontario, canada; 2department of ophthalmology, tongren hospital,
beijing, china; 3retinoblastoma solutions, university health
network, toronto, ontario, canada; 4daisy’s eye cancer fund,
oxford, united kingdom and sickkids foundation, toronto, canada;
5department of pediatrics, hospital for sick children, toronto,
ontario, canada
*correspondence to: brenda l. gallie, ontario cancer institute, rm 8-
415, 610 university avenue, toronto, ont, canada m5g 2m9.
e-mail: gallie@attglobal.net
received 25 july 2007; accepted 25 july 2007
recognized to be a major mechanism by which mutant tumor
suppressor genes initiate cancer [2,11,12]. however, m2 can also
involve all the other kinds of rb1 mutations. accurate molecularbased
genetic counseling is now available, since 93% of the rb1
mutations (m1 and m2) can be identified precisely in specialized
reference laboratories [5].
post-rb1 genomic changes driving
retinoblastoma progression
cancer progresses with clonal selection for cells carrying dna
mutations which promote an increased rate of division or the
indefinite survival of cancer stem cells, compared to cells that do not
carry such mutations [15?17]. identification of gain or loss of
genomic regions in retinoblastoma has been a first step to
discovering genes that contribute to progression (m3 to mn events)
[18]. we have narrowed the common regions of change in copy
number to ‘‘hotspots’’ containing candidate cancer genes kif14
(1q31), mycn (2p24), dek and e2f3 (6p22), and cdh11 (16q22)
[19?21]. gene expression and functional studies are used to identify
the causative genes [22].
we assembled markers for the ‘‘hotspots’’ for gain/loss into one
quantitative multiplex pcr (qm-pcr) to evaluate patterns of
genomic changes rapidly in 94 retinoblastoma tumors [23]. a
positive association was observed between 1q and 6p gain, and
a positive trend between 1q and mycn gain, but a negative
association between 16q22 loss andmycngain.we suggest that the
order of mn events contributing to progression in retinoblastoma
may be reflected by their frequency: 1q gain, the most frequent
change, may be important in most retinoblastoma tumors, while
16q22 loss or mycn gain may be mutually exclusive genomic
events in certain subsets of tumors. high-level mycn amplification
is a rare event.
the most frequently gained region (62% of retinoblastomas)
suggesting the location of oncogene(s), is 1q31, a dna region also
gained in several other important cancers. of the 12 genes in
the minimal region of 1q gain, only kif14, a mitotic kinesin,
showed very low expression in normal tissues and very high
expression in tumor samples [19]. kif14 function is activated by
genomic gain, amplification, and/or overexpression in nearly all
retinoblastoma tumors studied, after both alleles of the rb1 gene are
mutated. kif14 is also overexpressed in medulloblastoma and
breast cancer cell lines. high kif14 expression correlates with poor
outcome in patients with breast cancer [24] and non-small cell lung
cancer [22]. increasing kif14 expression in cell lines increases
cloning efficiency and reducing kif14 expression using silencing
rna reduces cloning efficiency, a measure of stem cell frequency
[22].
susceptible stem cell in developing retina
a constitutional mutation of the rb1 gene imposes a 22,500
relative risk (rr) for an infant to develop at least one retinoblastoma
tumor: 1 in 25,000 infants without an rb1 mutation will develop
retinoblastoma, compared to 90% of individuals with an rb1
mutation who will develop at least one retinoblastoma. since the
mean number of separate tumors in each affected eye is 3?4, the rr
for the retina to develop retinoblastoma is even higher.
the retinal cell type(s) that gives rise to retinoblastoma is
unknown. early onset tumors arise in the macular region that
differentiates first, while later onset tumors arise in the peripheral
retina that is the last area to differentiate, suggesting that tumor
initiation occurs in a retinal cell type that is present only in a narrow
developmental window close to terminal differentiation. based on
studies of morphology, immunohistochemistry and differentiation,
it was suggested that retinoblastoma arises from the photoreceptor
cells (reviewed [25]). however, small retinoblastoma tumors are
seen most commonly to emerge in the inner nuclear layer of the
retina [26], and murine models of retinoblastoma suggest that the
murine retinal cell that is susceptible to malignancy is also an inner
nuclear layer cell. the murine models are useful to dissect pathways
to cancer in the retina, but do not recapitulate the human situation, in
which a rare and unique retinal stem cell, not yet identified, is
extremely susceptible to the development of retinoblastoma when
rb1 function is lost.
progression of rb1/ cells to cancer
the vast majority of murine developing rb1/ retinal cells die.
we do not knowif human rb1/ retinal cells also usually die, but a
first step to retinoblastoma may be survival of an rb1/ cell that
forms a retinoma. retinomas are benign retinal tumors recognizable
by three features (elevated translucent retinal mass, calcification,
and surrounding pigment epithelial proliferation and pigmentation),
which are documented in persons with rb1 mutations [15], and may
progress to retinoblastoma [27] or stay unchanged throughout adult
life. once we identified the morphological characteristic of
retinoma, we discovered that more than 15% of eyes removed for
large retinoblastoma contain underlying but unsuspected retinomas.
like retinoblastoma, retinoma has two mutated rb1 alleles [17], but
does not show proliferation, aneuploidy or gene expression patterns
characteristic of retinoblastoma. for example, the proliferative
markers, ki67 and reactive p53, and the candidate oncogenes dek,
e2f3 and kif14 are not expressed in retinoma. the pro-apoptotic
protein p75ntr is expressed in retinoma but not retinoblastoma [16].
the senescence marker, p16, is expressed in retinoma but not retina
or retinoblastoma. the retinoblastoma family member p130, known
to be highly expressed at g0 [28] and linked to senescence [29],
is highly expressed in retinoma and retina but absent from
retinoblastoma.
drug resistance in retinoblastoma
the multidrug resistance (mdr) phenotype in human cancer is
often due to up-regulation of the mdr1 gene with increased
expression of p-glycoprotein [30]. in intraocular retinoblastoma, it
is not possible to correlate p-glycoprotein levels before therapy with
the outcome of chemotherapy since biopsies can incur an increased
risk of systemic spread [31]. in metastatic retinoblastoma, however,
p-glycoprotein expression before therapy correlates precisely with
failure of therapy, while undetectable p-glycoprotein correlates
with long-term remission or cure [32]. we have found that pglycoprotein
is increased in 33% of eyes with large retinoblastoma
tumors enucleated at diagnosis, and in 100% of eyes with large
tumors enucleated at failure of therapy [33]. this suggests that the
intrinsic presence of p-glycoprotein before therapy, and/or its
subsequent induction by therapy (chemotherapy, radiation), may
both be responsible for the resistance of large retinoblastoma tumors
to chemotherapy [34]. in contrast, eyes with medium and small
retinoblastoma tumors are often saved because these tumors
pediatr blood cancer doi 10.1002/pbc
1084 gallie et al.
frequently respond to chemotherapy [35], suggesting that pglycoprotein
is less likely to be a cause of failure of chemotherapy
in smaller tumors.
poor penetration of chemotherapy into the eye might also
contribute to drug resistance in retinoblastoma. the use of
cyclosporine a (csa) doubled the intravitreal carboplatin concentrations
in animals [36], possibly by circumventing the effect of
the highly expressed p-glycoprotein at the ‘‘blood-eye barrier’’.
intraocular retinoblastoma that failed chemotherapy despite csa
may express another drug resistance protein, multidrug resistance
protein (mrp) rather than p-glycoprotein, whereas retinoblastoma
that failed chemotherapy prior to our use of csa showed only
increased expression of p-glycoprotein [32]. there is presently no
effective inhibitor ofmrp[37]. retinoblastoma also expresses lung
resistance protein (lrp) intrinsically before chemotherapy [38].
the cell death p53 pathway, which is commonly inactivated in
human tumors, is generally functional in retinoblastoma, but
progression of retinoblastoma may sometimes be associated with
over-expression of the mdmx gene, an inhibitor of p53-dependent
apoptosis [39]. apoptosis is a prominent feature of retinoblastoma,
perhaps through non-p53 mechanisms. activation of apoptosis as a
therapy might reduce tumor size but not accomplish long term cure;
drugs that target the cancer stem cell of retinoblastoma will be a
better approach to long-term effective therapy.
second primary cancers in retinoblastoma
papers reporting risk of second primary cancers with radiation
have very little data on rb1 mutation carriers who did not receive
radiation [40?43]. the best data are reported as standardized
mortality ratios (smr) based on 144 survivors of retinoblastoma
who did not receive radiation (united kingdom, 1837?1950) [44].
in order to simplify comparison of data from different papers, we
will indicate ‘‘rr’’ although this important paper, which accessed
data from mortality records, reports smr rather than rr. the rr
for an individual with a germline rb1 mutation to develop other
tumor types is 37 if they were treated for retinoblastoma with
external beam irradiation [42], and 5 if they were not treated with
radiation [42]. these survivors of hereditary retinoblastoma who
were not exposed to radiotherapy showed an increased lifetime risk
for later-onset epithelial cancers (melanoma, non-melanoma skin,
bladder, corpus uteri, and lung) [43,45].
the rr for bone sarcoma was increased from 33 [42] to 475
(rr) when external beam radiation was used to treat retinoblastoma,
while the risk for soft tissue sarcoma did not change (rr 100,
no radiation; rr 100 with radiation). for persons with rb1
constitutional mutations, the bone sarcoma risk can be greatly
reduced by limiting the use of radiotherapy, while the high lung and
bladder cancer risk in older persons might be reduced by avoiding
tobacco, and reduced exposure to sunlight might reduce the excess
risk of melanoma.
the rr for trilateral retinoblastoma (intracranial primitive
neuroectodermal tumor in the pineal or suprasellar region in
children with bilateral retinoblastoma) is more than 100 in children
diagnosed from 1914 to 1984 [42]. however, a much higher rr of
650 was observed in children diagnosed from1972 to 1992 in
philadelphia [46]. while the demographics are similar in children
with bilateral and trilateral tumors, a far greater proportion of those
affected by trilateral disease had a family history (47%) of
retinoblastoma, than of those with bilateral disease (5%) [47?49].
the simplest explanation is that surveillance of familial retinoblastoma
allows the disease to be diagnosed and treated at a younger
age, since early treatment results in the best results for vision.
because the most common therapy for intraocular retinoblastoma
was external beam irradiation in the 1960?1990 period, children
with familial retinoblastoma often had radiation at a younger age
than children with non-familial disease. low-dose radiation to the
developing brain at a critical stage of development might increase
the risk of trilateral retinoblastoma in children with rb1 germline
mutations. indeed, in the netherlands where a tumor registry has
been maintained for a long time, increased mortality was noted in
children with bilateral retinoblastoma after 1945 compared to
before 1945, while mortality from unilateral retinoblastoma had
decreased [50]. in the 1990s chemotherapy largely replaced external
beam radiation for treatment of bilateral retinoblastoma and a
decrease in the incidence of trilateral retinoblastoma has been noted
[51,52].
classification of retinoblastoma
the new international intraocular retinoblastoma classification
(iirc) classifies eyes in accordance with the natural history of
retinoblastoma [35] (fig. 1). the first visible intraretinal retinoblastoma
tumors, which are discovered through surveillance
because of family history or genetic testing, appear as faint
opacifications of an otherwise transparent retina (iirc groups a
and b). the tumors then expand the retina, cause retinal detachment
or grow into the vitreous (iirc groups b and c), and migrate as
subretinal or vitreous seeds (iirc groups c and d) away from the
site of origin. seeds are usually hypoxic with no direct blood supply
and are relatively resistant to treatment. there is no information on
molecular correlation with the stages of intraocular disease.
intraocular retinoblastoma tumors are frequently necrotic and
apoptotic; calcification is almost pathognomic for retinoblastoma.
when the tumor extends as seeds anterior to the ora serrata of the
retina into the ciliary region or the anterior chamber, directly invades
the ciliary body, extends posteriorly to invade into the optic nerve, or
causes neovascularization of the iris, glaucoma or orbital cellulitis,
the risk of extraocular retinoblastoma is high. these eyes are called
iirc group e and require enucleation immediately, with timely,
pediatr blood cancer doi 10.1002/pbc
fig. 1. the international retinoblastoma classification is based on
the natural history of intraocular retinoblastoma and consensus of
appropriate therapies for stages of disease. [color figure can be viewed
in the online issue, which is available at www.interscience.wiley.com.]
retinoblastoma?a global perspective 1085
careful pathological examination to determine if extraocular spread
has already occurred, or is a significant risk because of tumor past
the cribriform plate into the optic nerve, or significantly into
choroid. the pathology determines the requirement for prolonged
systemic surveillance (such as bone marrow and cerebrospinal fluid
examinations, and/or whole-body magnetic resonance imaging,
mri), prophylactic therapy (such as chemotherapy), or intensive
treatment for metastatic disease. extraocular retinoblastoma may be
curable with combined intensive chemotherapy, radiation and
peripheral stem cell transplant. meningeal spread of retinoblastoma
is much more difficult to cure.
systematic development of therapy
randomized controlled trials provide a sound evidence base [53]
but observational studies, if done well, may provide useful data
[54,55]. a problem common to all rare diseases is the inability to
accrue enough patients to generate statistical power in clinical trials,
making it difficult, if not impossible, to conduct randomized
controlled trials [7,56]. in the case of retinoblastoma, the only study
designed as a randomized clinical trial closed early due to a low
patient accrual [3]. study of retinoblastoma is rendered more
difficult because treatment requires collaboration between ophthalmologists
and pediatric oncologists who are often not in the
same institutions with little opportunity to share care of the patients,
and by the complexity of two eyes in the same child having
independent stages and different responses to therapy, a major
challenge for trial designs.
retinoblastoma clinical trials
there are four multicenter clinical trials for retinoblastoma
currently open. the children’s oncology group (cog) has two
open trials. cog-aret0331 evaluates the event-free survival after
six cycles of chemotherapy (carboplatin/vincristine) with focal
therapy (laser, cryotherapy, brachytherapy) for group b eyes, and
assesses correlation of outcome with response rate after one cycle of
chemotherapy. cog-aret0332 prospectively determines the
prevalence of high-risk for metastatic disease based on pathological
features of eyes enucleated from unilateral retinoblastoma patients.
a similar study, ukccsg-rb-2005-11 is open in the uk:
unilateral retinoblastoma patients with enucleated eyes with no
high risk features are observed; those with high risk features but no
tumor at the cut end of the optic nerve in the enucleated eye receive
four cycles of adjuvant chemotherapy (cev), with intrathecal
cytarabine if needed; and those with tumor at the cut end of the optic
nerve receive six cycles of adjuvant cev, with intrathecal
cytarabine if needed, followed by orbital radiotherapy.
the toronto multicenter phase ii studies address treatment of
group b, c, and d eyes. two pilot studies from 1991?2000 and
from 2001?2004 established a chemotherapy dose-response effect,
a good cure rate and acceptable toxicity associated with high-dose
carboplatin, high-dose etoposide and standard-dose vincristine,
with additional high-dose 3-hr infusion of csa simultaneous with
the chemotherapy. since it was not possible to conduct these studies
as randomized clinical trials, the proportional success was evaluated
utilizing the best-available data from the internet world retinoblastoma
survey. most centers that have used chemotherapy with
the same drugs but no cyclosporine consider the endpoint to be
avoidance of external beam radiation and/or enucleation. using this
endpoint as the event, comparison of world data versus the toronto
pilot data showed event-free survival of 35% versus 57% (group d),
61% versus 67% (group c), and 67% versus 100% (group b),
respectively. the multicenter phase ii trial hfsc-ocrn-rb-2003
was opened in april 2005 to validate the outcomes in a multicenter
context. for the purpose of establishing the required sample size and
statistical analysis, we designated the ‘‘best’’ eye as the ‘‘index eye’’
for each child, although both eyes have retinoblastoma. children
with a group a eye are not eligible for the study, even if the other
worse eye is group b, c or d. this is because there will be an
inevitable bias toward an earlier declaration of failure for the worse
eye, since the good vision in the better groupaeye encourages early
enucleation of the worse eye to avoid systemic treatment. the
primary objective is to determine the proportion of eyes that remain
relapse-free while avoiding external beam radiation and/or
enucleation, using high-dose carboplatin/high-dose etoposide/
standard-dose vincristine with high-dose short cyclosporine infusions
in patients with newly diagnosed groups d and c (six cycles)
and b (three cycles), combined with focal therapy. the secondary
objective is to determine if toxicity is acceptable.
management of high-risk intraocular and
extraocular retinoblastoma
although when diagnosed early, retinoblastoma is curable in
96% of children, worldwide the majority of children with
retinoblastoma die of their disease. however, there are no open
multicenter clinical trials of therapy for extraocular retinoblastoma.
this is a prime area for international cooperation and best practice
guidelines, which presently do not exist. optic nerve involvement
by a few cells beyond the lamina cribosa is generally followed by
active surveillance (periodic lumbar puncture and mri head, orbit
and spine for 5 years). moderate optic nerve involvement beyond the
lamina cribosa is usually treated with three cycles of systemic
chemotherapy and then surveillance. extensive optic nerve involvement
beyond the lamina cribosa, extending to the cut end of the optic
nerve, or intracranial involvement, carry the worst prognosis, and
may require novel therapies and approaches to deliver therapy to the
meninges. at present, the toronto protocol for such disease includes
six-cycle systemic chemotherapy, intrathecal chemotherapy into the
ventricles via ommaya reservoir alternating with lumbar puncture,
radiation and autologous peripheral stem cell transplant. minor,
focal choroidal involvement and optic nerve involvement less than
1 mm beyond the lamina cribosa are not treated. moderate, severe
or multifocal choroidal involvement and scleral involvement are
treated with three cycles of systemic chemotherapy and surveillance
(periodic bone marrow examination and whole-body mri for
5 years, with increasing intervals the further from diagnosis).
orbital and extraorbital disease (most commonly bone marrow and
bone involvement) are treated with six-cycle systemic chemotherapy,
radiation, and autologous peripheral stem cell transplant
and have a better prognosis than central nervous system disease.
world retinoblastoma registry
we have conducted a retrospective world retinoblastoma
survey [57] using the internet, which provides baseline outcome
data from the largest number of children and eyes ever collected,
with all the eyes staged on one algorithm. data were collected on all
children presenting with retinoblastoma in collaborating eye centers
pediatr blood cancer doi 10.1002/pbc
1086 gallie et al.
in 1997?2001, through direct internet access to the database. the
survey included 1,487 children with 1,949 affected eyes from 25
retinoblastoma treatment centers on 5 continents. enucleation was
the primary treatment for 84% of unilaterally affected children,
particularly the most severely affected eyes in iirc groupsdand e.
chemotherapy with focal therapy was the primary treatment for
57% of eyes of bilaterally affected children. enucleation was the
primary treatment for 96% of iirc group e eyes, considered to be at
risk for extraocular tumor dissemination. accessibility to care was
inferred to be worse in asia (median age at diagnosis 22 months/
median follow-up 1.2 years) than in north america (12 months/
3 years) or europe (9 months/5 years).
the outcome of the least affected eye (the index eye) of each
child treated primarily with chemotherapy and focal therapy (laser,
cryotherapy, brachytherapy) was evaluated. preservation of the
index eye without the use of external beam radiation was considered
a success. the subsequent need to enucleate or irradiate the index
eye was considered a failure. the prognostic power of the new iirc
(fig. 1) was compared with the previous reese-ellsworth
classification [58]. kaplan?meier survival analysis of 254 index
eyes treated with chemotherapy and focal therapy showed that the
iirc had substantial predictive power (p<0.001). early-stage eyes
were failure-free for longer periods than late-stage eyes. the iirc
showed better prognostic power than the reese-ellsworth classification
to predict therapeutic success or failure in early-stage versus
late-stage eyes. the reese-ellsworth classification was formulated
in the 1960s, and was intended to predict outcomes of external beam
irradiation rather than outcomes of chemotherapy and focal therapy.
the world survey additionally evaluates access to diagnosis,
treatment trends and outcomes in a large global population, using
the standardized iirc classification. the internet survey data are
different and complementary to registry data [8]. the next step in
this international collaboration is to do a prospective observational
project by collecting the same data from each child diagnosed, at
the time of diagnosis, which will constitute a global retinoblastoma
registry.
strategies for prevention
and novel therapies
reducing tumor risk
stimulated by our predictions of improved clinical care as well as
net direct-cost savings (healthcare system savings, parental savings)
[6], we have developed highly sensitive and cost-effective
molecular identification of rb1 mutations for retinoblastoma
families [5]. significantly reduced healthcare direct-costs for
families have been confirmed, as a result of systematic molecular
diagnosis that focuses clinical resources for tumor surveillance on
the children who are shown to carry the rb1 mutation of the family,
rather than on the normal relatives. those without mutations need no
further medical surveillance or intervention [5,59].with 93% of all
families in our institution knowing their precise rb1 mutation
status, we now do very few clinical and under-anesthesia examinations
on normal children, the siblings or first cousins of children
with heritable retinoblastoma. the operating room and human
resources are used instead for children with retinoblastoma or high
risk of tumor.
infants who carry the rb1 mutant allele of their family are at
90% risk to develop retinoblastoma, and half of them have been
found to already have paramacular or macular tumors when
delivered prematurely at 36 weeks gestation. after birth, small
macular tumors have been treated with chemotherapy, laser, or
stereotactic radiation [60], depending on proximity of the tumors to
the macula and optic nerve. such infants subsequently develop more
tumors, but their best chance for central vision in one or both eyes is
achieved when the diagnosis of retinoblastoma is made before their
gestational due date since, if the pregnancy is allowed to go to term,
larger macular tumors develop and may be difficult to control,
resulting in worse central vision despite more intensive therapy.
we have estimated the number of ‘‘new’’ tumors that develop in
the eyes of children who did or did not receive chemotherapy for
tumors in the other eye. eyes with seeding were excluded to reduce
the chance that the small tumors seen were recurrences rather than
new tumors. for patients not treated with chemotherapy, the risk of
developing a newtumor after diagnosis was 2.2 times higher than for
patients who received chemotherapy. this fact is encouraging since
the chemotherapy appears to have accomplished some degree of
prevention of retinoblastoma.
the molecular definition of retinoma, the benign rb1/
precursor to retinoblastoma, opens the theoretical possibility of
prevention of retinoblastoma tumors in children identified prenatally
to carry their family’s mutation. it is unlikely that the m2 event
(loss of the second rb1 allele) can be blocked, since that may be a
common process occurring in all tissues at a lowrate. rather, them3
to mn subsequent genetic changes associated with retinoblastoma
progression, present an opportunity for intervention. for example,
the p16 protein is up-regulated in retinoma but lost through
unknown processes in retinoblastoma. therefore, stabilization of
p16 might become a prevention strategy. such approaches might
also reduce the risk for second primary tumors associated with the
rb1 mutation.
novel therapy targeting m3 to mn
progressive events
each m3 to mn molecular event is a potential therapeutic target.
for example, the significantly higher expression of kif14 in tumor
compared to normal tissue referred to above offers a promising
therapeutic ratio. early studies suggest that small interfering rna
(sirna) can reduce levels of kif14 mrna in cell lines and reduce
colony formation in vitro. such targeted modification of gene
expression might form the basis of future treatment strategies.
strategies to increase apoptosis are proposed to have therapeutic
potential [39], but may reduce tumor volumes without disabling the
cancer stem cell that is the source of recurrences. each recurrence
may have more genomic changes (mn) that ‘‘protect’’ the cancer
stem cell from therapies, and might be better targets for long-term
effective therapy.
development of therapies requires expensive, regulated drug
development, preclinical efficacy and toxicity testing depending on
valid models, then well designed and conducted clinical studies.
one drug development company (institute for oneworld health,
iowh) is not-for-profit, thereby able to target diseases with global
impact when large profits are not anticipated.
national retinoblastoma strategies
in the united kingdom, retinoblastoma care has been centralized
to two centers through a peer review system including participation
pediatr blood cancer doi 10.1002/pbc
retinoblastoma?a global perspective 1087
of parents (national specialist commissioning advisory group
[61] of the nhs). this enables a high standard of care accessible to
all children at reasonable cost [62]. many developed countries have
evolved a major center in retinoblastoma for every 30?60 children
with the disease.
the national retinoblastoma strategy (nrbs) is a canadian
network of concerned persons seeking to achieve optimal care
for canadian families. the goals of the nrbs are ambitious: no
child will lose both eyes to retinoblastoma; no child will die of
retinoblastoma; and each child and family will experience optimal
care, including access to timely diagnosis and appropriate care as
close to home as possible, with minimal disruption of family life. a
major focus of the nrbs is the development, dissemination, and
implementation of best practice guidelines, including the allocation
of care between primary, secondary and tertiary care providers.
the american academy of pediatrics has published a policy
statement describing the red reflex test of infants to detect significant
ocular abnormalities including retinoblastoma [63]. they
recommend that all infants have an examination of the red reflex
performed during the first 2 months of life by a pediatrician or other
primary care clinician trained in this examination technique. the red
reflex test should be performed in a darkened room on an infant
with his or her eyes open, preferably voluntarily, using a direct
ophthalmoscope held close to the examiner’s eye and approximately
an arm’s length away from the infant’s eyes. if the reflections of
the two eyes are equivalent, no follow-up is required; if there is
inequality in color, intensity or clarity of the reflection, or the
presence of opacities or white spots in either or both eyes, the red
reflex examination should be repeated with the pupils dilated, and
the child referred to an experienced, specialized, ophthalmologist.
in children at risk for retinoblastoma, repeat examination of the
retina with dilated pupils by an experienced ophthalmologist is
important for early identification of small tumors that can be treated
by laser or cryotherapy. examination under anaesthesia, with scleral
depression to visualize the whole retina, is standard in retinoblastoma
centers to facilitate diagnosis, treatment and follow-up. in less
developed countries, the expertise in retinoblastoma and anaesthesia
may both be lacking close to the child’s home.
once tumors are identified, the simple retinal drawing on
paper with colored pencils remains the most important sequential
documentation tool, since the location of all the tumors can be
mapped, and important details of the optic nerve and fovea, retinal
detachment, vitreous seeding, subretinal seeding, cryotherapy, and
laser scars, areas of hemorrhage, etc, recorded. wide-angle fundus
digital imaging has become a key tool in retinoblastoma centers,
with one instrument (retcamtm, clarity medical systems) most
commonly used worldwide, supporting sharing of images across the
internet. such imaging allows objective rather than subjective
documentation of the tumor status, staging, response to treatment,
recurrences, new tumors, and complications.
ultrasonography is an inexpensive and effective tool to confirm
the features of retinoblastoma: calcification and presence of a mass
lesion. it is reported to have 87% accuracy [64]. the more expensive
computerized axial tomography (ct scan) and/or mri are often
recommended in developed countries [65] but may not enhance
the quality of the diagnosis made by the clinical examination
and ultrasound. mri is not as specific as ct for diagnosis of
retinoblastoma, due to a lack of sensitivity in detecting calcification;
but on mri diagnoses such as coat’s disease are clearly differentiated
from retinoblastoma [66]. mri with gadolinium enhancement
is a good tool to determine the extension of retinoblastoma into
the optic nerve, orbital tissues and brain [67].
the survival rate of retinoblastoma depends on the extent of
disease at diagnosis and the availability of treatment.worldwide, by
far the commonest first sign of retinoblastoma is leukocoria: the
parents are usually the first to notice a white glint from the child’s
eye, ‘‘like a cat’s eye at night,’’ and this description is reported in all
languages worldwide (fig. 2). the mortality of retinoblastoma in
less developed countries could be greatly reduced by recognition of
leukocoria, referral to regional centers with expertise and simple
enucleation of eyes with tumor. accurate, timely pathological
determination of extent of tumor at the optic nerve and into choroid
is important so that prophylactic chemotherapy can be considered at
the time when it has a chance of controlling extraocular disease.
once orbital or widely metastatic disease is present, cure may not be
feasible.
global retinoblastoma
no clear geographic, racial, or environmental factors significantly
alter the incidence of retinoblastoma [8]. far more children
are diagnosed each year with retinoblastoma in india (1,519) and
china (1,134) than in the countries with the next highest number of
incident cases (320 in each of indonesia and nigeria), estimated
from the birth rate, infant death rate, and population. of the 8,198
children newly diagnosed with retinoblastoma each year around the
world in countries with available economic data, only 8% are
fortunate enough to be born in the top 30 countries in terms of health
care expenditure. although quality of health care does not correlate
precisely with health expenditure, it is clear that 92% of the world’s
children with retinoblastoma have minimal access to optimal care.
based on anecdotal evidence, only 10% of children in the poorest
pediatr blood cancer doi 10.1002/pbc
fig. 2. a,b: the white tumor filling this child’s right eye is obvious on
a family’s digital image, months before the correct diagnosis of
retinoblastoma is made. c: the white pupil is featured in this t-shirt and
poster delivering in swahili an important public message: ‘‘a white
reflection in a child’s eye could be a sign of cancer! if your child’s eye
looks like the one in the photograph, make sure a medical doctor checks
both eyes. untreated, children’s eye cancer is fatal, but when diagnosed
early it is very curable! don’t be slow. help your child to be a survivor!’’.
[color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
1088 gallie et al.
parts of the world will survive retinoblastoma. registry data from
europe from 1988 to 1997 indicate significant variation in overall
survival, ranging from 83% in eastern europe to 97% in the british
isles and north europe [8]. however, our hope is that the
enthusiastic support of families of patients with retinoblastoma for
each other, their ongoing concern for the future children who will be
affected, and the ease with which they can communicate electronically
around the world, will change the dramatic discrepancies in
outcomes.
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pediatr blood cancer doi 10.1002/pbc
1090 gallie et al.
brenda l. gallie, md,1* junyang zhao, md,2 kirk vandezande, phd,3
abigail white, bsc,4 and helen s.l. chan, md
5
introduction
retinoblastoma is a rare cancer of the eye that occurs in infancy
or early childhood [1] which presents dramatic contrasts.with early北京同仁医院眼肿瘤科赵军阳
diagnosis, retinoblastoma is easily cured. delayed diagnosis results
in visual impairment or blindness and risk of extraocular retinoblastoma
with faint hope of cure.
mortality of retinoblastoma in developed countries is about
4%, and deaths are more often from radiation-induced or sporadic
secondary malignancies than metastatic retinoblastoma. in stark
contrast, in less developed contexts, mortality may be as high as
90% because of both late diagnosis and lack of expert resources
focused on retinoblastoma.
the scientific approach to retinoblastoma also reveals stark
contrasts between the evident clarity of understanding of cancer
established through the study of retinoblastoma [2] and the failure,
for many reasons, to apply clinical science to development of
therapies for this disease [3]. the rb1 gene [4] is the first tumor
suppressor gene identified, and sparked an explosion of the study of
cell cycle control in cancer. the highest level of sensitivity in
molecular detection of rb1 mutations in individual retinoblastoma
families [5] has been achieved and the impact of this diagnostic
test, in conjunction with superior quality of care for retinoblastoma,
on the reduction of healthcare cost has been evaluated scientifically
[5][6]. by contrast, basic approaches to early diagnosis and effective
therapy are lacking in many emerging countries. randomized
controlled clinical trials and evidence-based medicine have very
effectively changed the outcomes of cancers in children in general,
but this has not been the case for retinoblastoma [3], in part
because insufficient patients have been available to power clinical
trials [7]. the many obstacles of how to apply clinical science to the
treatment of retinoblastoma might be solved by real global
collaboration.
basic causes of retinoblastoma
cancer susceptibility associated with rb1 mutation
the incidence of retinoblastoma is 1 in 15,000?20,000 live
births, regardless of sex, race, or geography [8]. most children are
diagnosed before 3 years of age. knudson conceived the ‘‘two-hit
hypothesis’’ by recognizing that hereditary retinoblastoma was
diagnosed at a younger age than unilateral non-familial retinoblastoma.
this theory suggested only two rate-limiting events in the
initiation of retinoblastoma: two somatic events in non-heritable
(always unilateral disease), or one somatic event after a first,
heritable event (usually bilateral disease) [9]. based on retinoblastoma,
the broad concept of tumor suppressor genes was conceived
[10], proven [2,11,12], and loss of heterozygosity was recognized to
be the major mechanism by which tumor suppressor genes initiate
cancer. rb1 [4] was cloned by first identifying a dna fragment at
chromosome 13q14 that was totally missing in one retinoblastoma
tumor [13]. the rb1 gene is relatively large and mutations can occur
anywhere in its 27 exons or the promoter region [5].
all retinoblastoma tumors are missing rb1 gene function, due to
mutations (m) of the first rb1 allele (m1) and then the second rb1
allele (m2) in the cell in the developing retina that ultimately forms a
tumor. of all the children with retinoblastoma, 60% developed a
tumor because both m1 and m2 occurred in one single retinal cell
that became their unilateral tumor, and their relatives are not at risk.
in 40% of children, the mutation in the first allele (m1) is carried in
constitutional cells, and may have been inherited from a parent, or
have arisen in a gamete before conception or in only a fraction of the
cells of the embryo resulting in mosaicism for the mutant rb1 allele
[14]. individuals with one constitutional mutant rb1 allele are
completely normal except for high cancer susceptibility. they
usually (90%) develop bilateral retinoblastoma, but may also
develop unilateral disease or no tumors.
rb1 gene function can be lost in many ways [5]: deletion of all or
part of the gene, its translocation onto another chromosome,
mutations that alter rna splicing, or point mutations leading to
truncation of translation or amino acid substitution. in tumors, but
not constitutional cells, methylation of the rb1 promoter can also
eliminate the function of the rb1 gene. the most frequent m2 event
is loss of heterozygosity, in which large regions containing the m1
mutant allele are reduplicated on the second allele. this is widely
the rb1 gene is important in all human cancers. studies of
human retinoblastoma point to a rare retinal cell with extreme
dependency on rb1 for initiation but not progression to full
malignancy. in developed countries, genetic testing within affected
families can predict children at high risk of retinoblastoma before
birth; chemotherapy with local therapy often saves eyes and vision;
and mortality is 4%. in less developed countries where 92% of
children with retinoblastoma are born, mortality reaches 90%.
global collaboration is building for the dramatic change in mortality
that awareness, simple expertise and therapies could achieve in less
developed countries. pediatr blood cancer 2007;49:1083?1090.
2007 wiley-liss, inc.
key words: retinoblastoma; suppressor genes
2007 wiley-liss, inc.
doi 10.1002/pbc.21350
??????
1retinoblastoma program, hospital for sick children and applied
molecular oncology, ontario cancer institute/princess margaret
hospital, university health network, university of toronto, toronto,
ontario, canada; 2department of ophthalmology, tongren hospital,
beijing, china; 3retinoblastoma solutions, university health
network, toronto, ontario, canada; 4daisy’s eye cancer fund,
oxford, united kingdom and sickkids foundation, toronto, canada;
5department of pediatrics, hospital for sick children, toronto,
ontario, canada
*correspondence to: brenda l. gallie, ontario cancer institute, rm 8-
415, 610 university avenue, toronto, ont, canada m5g 2m9.
e-mail: gallie@attglobal.net
received 25 july 2007; accepted 25 july 2007
recognized to be a major mechanism by which mutant tumor
suppressor genes initiate cancer [2,11,12]. however, m2 can also
involve all the other kinds of rb1 mutations. accurate molecularbased
genetic counseling is now available, since 93% of the rb1
mutations (m1 and m2) can be identified precisely in specialized
reference laboratories [5].
post-rb1 genomic changes driving
retinoblastoma progression
cancer progresses with clonal selection for cells carrying dna
mutations which promote an increased rate of division or the
indefinite survival of cancer stem cells, compared to cells that do not
carry such mutations [15?17]. identification of gain or loss of
genomic regions in retinoblastoma has been a first step to
discovering genes that contribute to progression (m3 to mn events)
[18]. we have narrowed the common regions of change in copy
number to ‘‘hotspots’’ containing candidate cancer genes kif14
(1q31), mycn (2p24), dek and e2f3 (6p22), and cdh11 (16q22)
[19?21]. gene expression and functional studies are used to identify
the causative genes [22].
we assembled markers for the ‘‘hotspots’’ for gain/loss into one
quantitative multiplex pcr (qm-pcr) to evaluate patterns of
genomic changes rapidly in 94 retinoblastoma tumors [23]. a
positive association was observed between 1q and 6p gain, and
a positive trend between 1q and mycn gain, but a negative
association between 16q22 loss andmycngain.we suggest that the
order of mn events contributing to progression in retinoblastoma
may be reflected by their frequency: 1q gain, the most frequent
change, may be important in most retinoblastoma tumors, while
16q22 loss or mycn gain may be mutually exclusive genomic
events in certain subsets of tumors. high-level mycn amplification
is a rare event.
the most frequently gained region (62% of retinoblastomas)
suggesting the location of oncogene(s), is 1q31, a dna region also
gained in several other important cancers. of the 12 genes in
the minimal region of 1q gain, only kif14, a mitotic kinesin,
showed very low expression in normal tissues and very high
expression in tumor samples [19]. kif14 function is activated by
genomic gain, amplification, and/or overexpression in nearly all
retinoblastoma tumors studied, after both alleles of the rb1 gene are
mutated. kif14 is also overexpressed in medulloblastoma and
breast cancer cell lines. high kif14 expression correlates with poor
outcome in patients with breast cancer [24] and non-small cell lung
cancer [22]. increasing kif14 expression in cell lines increases
cloning efficiency and reducing kif14 expression using silencing
rna reduces cloning efficiency, a measure of stem cell frequency
[22].
susceptible stem cell in developing retina
a constitutional mutation of the rb1 gene imposes a 22,500
relative risk (rr) for an infant to develop at least one retinoblastoma
tumor: 1 in 25,000 infants without an rb1 mutation will develop
retinoblastoma, compared to 90% of individuals with an rb1
mutation who will develop at least one retinoblastoma. since the
mean number of separate tumors in each affected eye is 3?4, the rr
for the retina to develop retinoblastoma is even higher.
the retinal cell type(s) that gives rise to retinoblastoma is
unknown. early onset tumors arise in the macular region that
differentiates first, while later onset tumors arise in the peripheral
retina that is the last area to differentiate, suggesting that tumor
initiation occurs in a retinal cell type that is present only in a narrow
developmental window close to terminal differentiation. based on
studies of morphology, immunohistochemistry and differentiation,
it was suggested that retinoblastoma arises from the photoreceptor
cells (reviewed [25]). however, small retinoblastoma tumors are
seen most commonly to emerge in the inner nuclear layer of the
retina [26], and murine models of retinoblastoma suggest that the
murine retinal cell that is susceptible to malignancy is also an inner
nuclear layer cell. the murine models are useful to dissect pathways
to cancer in the retina, but do not recapitulate the human situation, in
which a rare and unique retinal stem cell, not yet identified, is
extremely susceptible to the development of retinoblastoma when
rb1 function is lost.
progression of rb1/ cells to cancer
the vast majority of murine developing rb1/ retinal cells die.
we do not knowif human rb1/ retinal cells also usually die, but a
first step to retinoblastoma may be survival of an rb1/ cell that
forms a retinoma. retinomas are benign retinal tumors recognizable
by three features (elevated translucent retinal mass, calcification,
and surrounding pigment epithelial proliferation and pigmentation),
which are documented in persons with rb1 mutations [15], and may
progress to retinoblastoma [27] or stay unchanged throughout adult
life. once we identified the morphological characteristic of
retinoma, we discovered that more than 15% of eyes removed for
large retinoblastoma contain underlying but unsuspected retinomas.
like retinoblastoma, retinoma has two mutated rb1 alleles [17], but
does not show proliferation, aneuploidy or gene expression patterns
characteristic of retinoblastoma. for example, the proliferative
markers, ki67 and reactive p53, and the candidate oncogenes dek,
e2f3 and kif14 are not expressed in retinoma. the pro-apoptotic
protein p75ntr is expressed in retinoma but not retinoblastoma [16].
the senescence marker, p16, is expressed in retinoma but not retina
or retinoblastoma. the retinoblastoma family member p130, known
to be highly expressed at g0 [28] and linked to senescence [29],
is highly expressed in retinoma and retina but absent from
retinoblastoma.
drug resistance in retinoblastoma
the multidrug resistance (mdr) phenotype in human cancer is
often due to up-regulation of the mdr1 gene with increased
expression of p-glycoprotein [30]. in intraocular retinoblastoma, it
is not possible to correlate p-glycoprotein levels before therapy with
the outcome of chemotherapy since biopsies can incur an increased
risk of systemic spread [31]. in metastatic retinoblastoma, however,
p-glycoprotein expression before therapy correlates precisely with
failure of therapy, while undetectable p-glycoprotein correlates
with long-term remission or cure [32]. we have found that pglycoprotein
is increased in 33% of eyes with large retinoblastoma
tumors enucleated at diagnosis, and in 100% of eyes with large
tumors enucleated at failure of therapy [33]. this suggests that the
intrinsic presence of p-glycoprotein before therapy, and/or its
subsequent induction by therapy (chemotherapy, radiation), may
both be responsible for the resistance of large retinoblastoma tumors
to chemotherapy [34]. in contrast, eyes with medium and small
retinoblastoma tumors are often saved because these tumors
pediatr blood cancer doi 10.1002/pbc
1084 gallie et al.
frequently respond to chemotherapy [35], suggesting that pglycoprotein
is less likely to be a cause of failure of chemotherapy
in smaller tumors.
poor penetration of chemotherapy into the eye might also
contribute to drug resistance in retinoblastoma. the use of
cyclosporine a (csa) doubled the intravitreal carboplatin concentrations
in animals [36], possibly by circumventing the effect of
the highly expressed p-glycoprotein at the ‘‘blood-eye barrier’’.
intraocular retinoblastoma that failed chemotherapy despite csa
may express another drug resistance protein, multidrug resistance
protein (mrp) rather than p-glycoprotein, whereas retinoblastoma
that failed chemotherapy prior to our use of csa showed only
increased expression of p-glycoprotein [32]. there is presently no
effective inhibitor ofmrp[37]. retinoblastoma also expresses lung
resistance protein (lrp) intrinsically before chemotherapy [38].
the cell death p53 pathway, which is commonly inactivated in
human tumors, is generally functional in retinoblastoma, but
progression of retinoblastoma may sometimes be associated with
over-expression of the mdmx gene, an inhibitor of p53-dependent
apoptosis [39]. apoptosis is a prominent feature of retinoblastoma,
perhaps through non-p53 mechanisms. activation of apoptosis as a
therapy might reduce tumor size but not accomplish long term cure;
drugs that target the cancer stem cell of retinoblastoma will be a
better approach to long-term effective therapy.
second primary cancers in retinoblastoma
papers reporting risk of second primary cancers with radiation
have very little data on rb1 mutation carriers who did not receive
radiation [40?43]. the best data are reported as standardized
mortality ratios (smr) based on 144 survivors of retinoblastoma
who did not receive radiation (united kingdom, 1837?1950) [44].
in order to simplify comparison of data from different papers, we
will indicate ‘‘rr’’ although this important paper, which accessed
data from mortality records, reports smr rather than rr. the rr
for an individual with a germline rb1 mutation to develop other
tumor types is 37 if they were treated for retinoblastoma with
external beam irradiation [42], and 5 if they were not treated with
radiation [42]. these survivors of hereditary retinoblastoma who
were not exposed to radiotherapy showed an increased lifetime risk
for later-onset epithelial cancers (melanoma, non-melanoma skin,
bladder, corpus uteri, and lung) [43,45].
the rr for bone sarcoma was increased from 33 [42] to 475
(rr) when external beam radiation was used to treat retinoblastoma,
while the risk for soft tissue sarcoma did not change (rr 100,
no radiation; rr 100 with radiation). for persons with rb1
constitutional mutations, the bone sarcoma risk can be greatly
reduced by limiting the use of radiotherapy, while the high lung and
bladder cancer risk in older persons might be reduced by avoiding
tobacco, and reduced exposure to sunlight might reduce the excess
risk of melanoma.
the rr for trilateral retinoblastoma (intracranial primitive
neuroectodermal tumor in the pineal or suprasellar region in
children with bilateral retinoblastoma) is more than 100 in children
diagnosed from 1914 to 1984 [42]. however, a much higher rr of
650 was observed in children diagnosed from1972 to 1992 in
philadelphia [46]. while the demographics are similar in children
with bilateral and trilateral tumors, a far greater proportion of those
affected by trilateral disease had a family history (47%) of
retinoblastoma, than of those with bilateral disease (5%) [47?49].
the simplest explanation is that surveillance of familial retinoblastoma
allows the disease to be diagnosed and treated at a younger
age, since early treatment results in the best results for vision.
because the most common therapy for intraocular retinoblastoma
was external beam irradiation in the 1960?1990 period, children
with familial retinoblastoma often had radiation at a younger age
than children with non-familial disease. low-dose radiation to the
developing brain at a critical stage of development might increase
the risk of trilateral retinoblastoma in children with rb1 germline
mutations. indeed, in the netherlands where a tumor registry has
been maintained for a long time, increased mortality was noted in
children with bilateral retinoblastoma after 1945 compared to
before 1945, while mortality from unilateral retinoblastoma had
decreased [50]. in the 1990s chemotherapy largely replaced external
beam radiation for treatment of bilateral retinoblastoma and a
decrease in the incidence of trilateral retinoblastoma has been noted
[51,52].
classification of retinoblastoma
the new international intraocular retinoblastoma classification
(iirc) classifies eyes in accordance with the natural history of
retinoblastoma [35] (fig. 1). the first visible intraretinal retinoblastoma
tumors, which are discovered through surveillance
because of family history or genetic testing, appear as faint
opacifications of an otherwise transparent retina (iirc groups a
and b). the tumors then expand the retina, cause retinal detachment
or grow into the vitreous (iirc groups b and c), and migrate as
subretinal or vitreous seeds (iirc groups c and d) away from the
site of origin. seeds are usually hypoxic with no direct blood supply
and are relatively resistant to treatment. there is no information on
molecular correlation with the stages of intraocular disease.
intraocular retinoblastoma tumors are frequently necrotic and
apoptotic; calcification is almost pathognomic for retinoblastoma.
when the tumor extends as seeds anterior to the ora serrata of the
retina into the ciliary region or the anterior chamber, directly invades
the ciliary body, extends posteriorly to invade into the optic nerve, or
causes neovascularization of the iris, glaucoma or orbital cellulitis,
the risk of extraocular retinoblastoma is high. these eyes are called
iirc group e and require enucleation immediately, with timely,
pediatr blood cancer doi 10.1002/pbc
fig. 1. the international retinoblastoma classification is based on
the natural history of intraocular retinoblastoma and consensus of
appropriate therapies for stages of disease. [color figure can be viewed
in the online issue, which is available at www.interscience.wiley.com.]
retinoblastoma?a global perspective 1085
careful pathological examination to determine if extraocular spread
has already occurred, or is a significant risk because of tumor past
the cribriform plate into the optic nerve, or significantly into
choroid. the pathology determines the requirement for prolonged
systemic surveillance (such as bone marrow and cerebrospinal fluid
examinations, and/or whole-body magnetic resonance imaging,
mri), prophylactic therapy (such as chemotherapy), or intensive
treatment for metastatic disease. extraocular retinoblastoma may be
curable with combined intensive chemotherapy, radiation and
peripheral stem cell transplant. meningeal spread of retinoblastoma
is much more difficult to cure.
systematic development of therapy
randomized controlled trials provide a sound evidence base [53]
but observational studies, if done well, may provide useful data
[54,55]. a problem common to all rare diseases is the inability to
accrue enough patients to generate statistical power in clinical trials,
making it difficult, if not impossible, to conduct randomized
controlled trials [7,56]. in the case of retinoblastoma, the only study
designed as a randomized clinical trial closed early due to a low
patient accrual [3]. study of retinoblastoma is rendered more
difficult because treatment requires collaboration between ophthalmologists
and pediatric oncologists who are often not in the
same institutions with little opportunity to share care of the patients,
and by the complexity of two eyes in the same child having
independent stages and different responses to therapy, a major
challenge for trial designs.
retinoblastoma clinical trials
there are four multicenter clinical trials for retinoblastoma
currently open. the children’s oncology group (cog) has two
open trials. cog-aret0331 evaluates the event-free survival after
six cycles of chemotherapy (carboplatin/vincristine) with focal
therapy (laser, cryotherapy, brachytherapy) for group b eyes, and
assesses correlation of outcome with response rate after one cycle of
chemotherapy. cog-aret0332 prospectively determines the
prevalence of high-risk for metastatic disease based on pathological
features of eyes enucleated from unilateral retinoblastoma patients.
a similar study, ukccsg-rb-2005-11 is open in the uk:
unilateral retinoblastoma patients with enucleated eyes with no
high risk features are observed; those with high risk features but no
tumor at the cut end of the optic nerve in the enucleated eye receive
four cycles of adjuvant chemotherapy (cev), with intrathecal
cytarabine if needed; and those with tumor at the cut end of the optic
nerve receive six cycles of adjuvant cev, with intrathecal
cytarabine if needed, followed by orbital radiotherapy.
the toronto multicenter phase ii studies address treatment of
group b, c, and d eyes. two pilot studies from 1991?2000 and
from 2001?2004 established a chemotherapy dose-response effect,
a good cure rate and acceptable toxicity associated with high-dose
carboplatin, high-dose etoposide and standard-dose vincristine,
with additional high-dose 3-hr infusion of csa simultaneous with
the chemotherapy. since it was not possible to conduct these studies
as randomized clinical trials, the proportional success was evaluated
utilizing the best-available data from the internet world retinoblastoma
survey. most centers that have used chemotherapy with
the same drugs but no cyclosporine consider the endpoint to be
avoidance of external beam radiation and/or enucleation. using this
endpoint as the event, comparison of world data versus the toronto
pilot data showed event-free survival of 35% versus 57% (group d),
61% versus 67% (group c), and 67% versus 100% (group b),
respectively. the multicenter phase ii trial hfsc-ocrn-rb-2003
was opened in april 2005 to validate the outcomes in a multicenter
context. for the purpose of establishing the required sample size and
statistical analysis, we designated the ‘‘best’’ eye as the ‘‘index eye’’
for each child, although both eyes have retinoblastoma. children
with a group a eye are not eligible for the study, even if the other
worse eye is group b, c or d. this is because there will be an
inevitable bias toward an earlier declaration of failure for the worse
eye, since the good vision in the better groupaeye encourages early
enucleation of the worse eye to avoid systemic treatment. the
primary objective is to determine the proportion of eyes that remain
relapse-free while avoiding external beam radiation and/or
enucleation, using high-dose carboplatin/high-dose etoposide/
standard-dose vincristine with high-dose short cyclosporine infusions
in patients with newly diagnosed groups d and c (six cycles)
and b (three cycles), combined with focal therapy. the secondary
objective is to determine if toxicity is acceptable.
management of high-risk intraocular and
extraocular retinoblastoma
although when diagnosed early, retinoblastoma is curable in
96% of children, worldwide the majority of children with
retinoblastoma die of their disease. however, there are no open
multicenter clinical trials of therapy for extraocular retinoblastoma.
this is a prime area for international cooperation and best practice
guidelines, which presently do not exist. optic nerve involvement
by a few cells beyond the lamina cribosa is generally followed by
active surveillance (periodic lumbar puncture and mri head, orbit
and spine for 5 years). moderate optic nerve involvement beyond the
lamina cribosa is usually treated with three cycles of systemic
chemotherapy and then surveillance. extensive optic nerve involvement
beyond the lamina cribosa, extending to the cut end of the optic
nerve, or intracranial involvement, carry the worst prognosis, and
may require novel therapies and approaches to deliver therapy to the
meninges. at present, the toronto protocol for such disease includes
six-cycle systemic chemotherapy, intrathecal chemotherapy into the
ventricles via ommaya reservoir alternating with lumbar puncture,
radiation and autologous peripheral stem cell transplant. minor,
focal choroidal involvement and optic nerve involvement less than
1 mm beyond the lamina cribosa are not treated. moderate, severe
or multifocal choroidal involvement and scleral involvement are
treated with three cycles of systemic chemotherapy and surveillance
(periodic bone marrow examination and whole-body mri for
5 years, with increasing intervals the further from diagnosis).
orbital and extraorbital disease (most commonly bone marrow and
bone involvement) are treated with six-cycle systemic chemotherapy,
radiation, and autologous peripheral stem cell transplant
and have a better prognosis than central nervous system disease.
world retinoblastoma registry
we have conducted a retrospective world retinoblastoma
survey [57] using the internet, which provides baseline outcome
data from the largest number of children and eyes ever collected,
with all the eyes staged on one algorithm. data were collected on all
children presenting with retinoblastoma in collaborating eye centers
pediatr blood cancer doi 10.1002/pbc
1086 gallie et al.
in 1997?2001, through direct internet access to the database. the
survey included 1,487 children with 1,949 affected eyes from 25
retinoblastoma treatment centers on 5 continents. enucleation was
the primary treatment for 84% of unilaterally affected children,
particularly the most severely affected eyes in iirc groupsdand e.
chemotherapy with focal therapy was the primary treatment for
57% of eyes of bilaterally affected children. enucleation was the
primary treatment for 96% of iirc group e eyes, considered to be at
risk for extraocular tumor dissemination. accessibility to care was
inferred to be worse in asia (median age at diagnosis 22 months/
median follow-up 1.2 years) than in north america (12 months/
3 years) or europe (9 months/5 years).
the outcome of the least affected eye (the index eye) of each
child treated primarily with chemotherapy and focal therapy (laser,
cryotherapy, brachytherapy) was evaluated. preservation of the
index eye without the use of external beam radiation was considered
a success. the subsequent need to enucleate or irradiate the index
eye was considered a failure. the prognostic power of the new iirc
(fig. 1) was compared with the previous reese-ellsworth
classification [58]. kaplan?meier survival analysis of 254 index
eyes treated with chemotherapy and focal therapy showed that the
iirc had substantial predictive power (p<0.001). early-stage eyes
were failure-free for longer periods than late-stage eyes. the iirc
showed better prognostic power than the reese-ellsworth classification
to predict therapeutic success or failure in early-stage versus
late-stage eyes. the reese-ellsworth classification was formulated
in the 1960s, and was intended to predict outcomes of external beam
irradiation rather than outcomes of chemotherapy and focal therapy.
the world survey additionally evaluates access to diagnosis,
treatment trends and outcomes in a large global population, using
the standardized iirc classification. the internet survey data are
different and complementary to registry data [8]. the next step in
this international collaboration is to do a prospective observational
project by collecting the same data from each child diagnosed, at
the time of diagnosis, which will constitute a global retinoblastoma
registry.
strategies for prevention
and novel therapies
reducing tumor risk
stimulated by our predictions of improved clinical care as well as
net direct-cost savings (healthcare system savings, parental savings)
[6], we have developed highly sensitive and cost-effective
molecular identification of rb1 mutations for retinoblastoma
families [5]. significantly reduced healthcare direct-costs for
families have been confirmed, as a result of systematic molecular
diagnosis that focuses clinical resources for tumor surveillance on
the children who are shown to carry the rb1 mutation of the family,
rather than on the normal relatives. those without mutations need no
further medical surveillance or intervention [5,59].with 93% of all
families in our institution knowing their precise rb1 mutation
status, we now do very few clinical and under-anesthesia examinations
on normal children, the siblings or first cousins of children
with heritable retinoblastoma. the operating room and human
resources are used instead for children with retinoblastoma or high
risk of tumor.
infants who carry the rb1 mutant allele of their family are at
90% risk to develop retinoblastoma, and half of them have been
found to already have paramacular or macular tumors when
delivered prematurely at 36 weeks gestation. after birth, small
macular tumors have been treated with chemotherapy, laser, or
stereotactic radiation [60], depending on proximity of the tumors to
the macula and optic nerve. such infants subsequently develop more
tumors, but their best chance for central vision in one or both eyes is
achieved when the diagnosis of retinoblastoma is made before their
gestational due date since, if the pregnancy is allowed to go to term,
larger macular tumors develop and may be difficult to control,
resulting in worse central vision despite more intensive therapy.
we have estimated the number of ‘‘new’’ tumors that develop in
the eyes of children who did or did not receive chemotherapy for
tumors in the other eye. eyes with seeding were excluded to reduce
the chance that the small tumors seen were recurrences rather than
new tumors. for patients not treated with chemotherapy, the risk of
developing a newtumor after diagnosis was 2.2 times higher than for
patients who received chemotherapy. this fact is encouraging since
the chemotherapy appears to have accomplished some degree of
prevention of retinoblastoma.
the molecular definition of retinoma, the benign rb1/
precursor to retinoblastoma, opens the theoretical possibility of
prevention of retinoblastoma tumors in children identified prenatally
to carry their family’s mutation. it is unlikely that the m2 event
(loss of the second rb1 allele) can be blocked, since that may be a
common process occurring in all tissues at a lowrate. rather, them3
to mn subsequent genetic changes associated with retinoblastoma
progression, present an opportunity for intervention. for example,
the p16 protein is up-regulated in retinoma but lost through
unknown processes in retinoblastoma. therefore, stabilization of
p16 might become a prevention strategy. such approaches might
also reduce the risk for second primary tumors associated with the
rb1 mutation.
novel therapy targeting m3 to mn
progressive events
each m3 to mn molecular event is a potential therapeutic target.
for example, the significantly higher expression of kif14 in tumor
compared to normal tissue referred to above offers a promising
therapeutic ratio. early studies suggest that small interfering rna
(sirna) can reduce levels of kif14 mrna in cell lines and reduce
colony formation in vitro. such targeted modification of gene
expression might form the basis of future treatment strategies.
strategies to increase apoptosis are proposed to have therapeutic
potential [39], but may reduce tumor volumes without disabling the
cancer stem cell that is the source of recurrences. each recurrence
may have more genomic changes (mn) that ‘‘protect’’ the cancer
stem cell from therapies, and might be better targets for long-term
effective therapy.
development of therapies requires expensive, regulated drug
development, preclinical efficacy and toxicity testing depending on
valid models, then well designed and conducted clinical studies.
one drug development company (institute for oneworld health,
iowh) is not-for-profit, thereby able to target diseases with global
impact when large profits are not anticipated.
national retinoblastoma strategies
in the united kingdom, retinoblastoma care has been centralized
to two centers through a peer review system including participation
pediatr blood cancer doi 10.1002/pbc
retinoblastoma?a global perspective 1087
of parents (national specialist commissioning advisory group
[61] of the nhs). this enables a high standard of care accessible to
all children at reasonable cost [62]. many developed countries have
evolved a major center in retinoblastoma for every 30?60 children
with the disease.
the national retinoblastoma strategy (nrbs) is a canadian
network of concerned persons seeking to achieve optimal care
for canadian families. the goals of the nrbs are ambitious: no
child will lose both eyes to retinoblastoma; no child will die of
retinoblastoma; and each child and family will experience optimal
care, including access to timely diagnosis and appropriate care as
close to home as possible, with minimal disruption of family life. a
major focus of the nrbs is the development, dissemination, and
implementation of best practice guidelines, including the allocation
of care between primary, secondary and tertiary care providers.
the american academy of pediatrics has published a policy
statement describing the red reflex test of infants to detect significant
ocular abnormalities including retinoblastoma [63]. they
recommend that all infants have an examination of the red reflex
performed during the first 2 months of life by a pediatrician or other
primary care clinician trained in this examination technique. the red
reflex test should be performed in a darkened room on an infant
with his or her eyes open, preferably voluntarily, using a direct
ophthalmoscope held close to the examiner’s eye and approximately
an arm’s length away from the infant’s eyes. if the reflections of
the two eyes are equivalent, no follow-up is required; if there is
inequality in color, intensity or clarity of the reflection, or the
presence of opacities or white spots in either or both eyes, the red
reflex examination should be repeated with the pupils dilated, and
the child referred to an experienced, specialized, ophthalmologist.
in children at risk for retinoblastoma, repeat examination of the
retina with dilated pupils by an experienced ophthalmologist is
important for early identification of small tumors that can be treated
by laser or cryotherapy. examination under anaesthesia, with scleral
depression to visualize the whole retina, is standard in retinoblastoma
centers to facilitate diagnosis, treatment and follow-up. in less
developed countries, the expertise in retinoblastoma and anaesthesia
may both be lacking close to the child’s home.
once tumors are identified, the simple retinal drawing on
paper with colored pencils remains the most important sequential
documentation tool, since the location of all the tumors can be
mapped, and important details of the optic nerve and fovea, retinal
detachment, vitreous seeding, subretinal seeding, cryotherapy, and
laser scars, areas of hemorrhage, etc, recorded. wide-angle fundus
digital imaging has become a key tool in retinoblastoma centers,
with one instrument (retcamtm, clarity medical systems) most
commonly used worldwide, supporting sharing of images across the
internet. such imaging allows objective rather than subjective
documentation of the tumor status, staging, response to treatment,
recurrences, new tumors, and complications.
ultrasonography is an inexpensive and effective tool to confirm
the features of retinoblastoma: calcification and presence of a mass
lesion. it is reported to have 87% accuracy [64]. the more expensive
computerized axial tomography (ct scan) and/or mri are often
recommended in developed countries [65] but may not enhance
the quality of the diagnosis made by the clinical examination
and ultrasound. mri is not as specific as ct for diagnosis of
retinoblastoma, due to a lack of sensitivity in detecting calcification;
but on mri diagnoses such as coat’s disease are clearly differentiated
from retinoblastoma [66]. mri with gadolinium enhancement
is a good tool to determine the extension of retinoblastoma into
the optic nerve, orbital tissues and brain [67].
the survival rate of retinoblastoma depends on the extent of
disease at diagnosis and the availability of treatment.worldwide, by
far the commonest first sign of retinoblastoma is leukocoria: the
parents are usually the first to notice a white glint from the child’s
eye, ‘‘like a cat’s eye at night,’’ and this description is reported in all
languages worldwide (fig. 2). the mortality of retinoblastoma in
less developed countries could be greatly reduced by recognition of
leukocoria, referral to regional centers with expertise and simple
enucleation of eyes with tumor. accurate, timely pathological
determination of extent of tumor at the optic nerve and into choroid
is important so that prophylactic chemotherapy can be considered at
the time when it has a chance of controlling extraocular disease.
once orbital or widely metastatic disease is present, cure may not be
feasible.
global retinoblastoma
no clear geographic, racial, or environmental factors significantly
alter the incidence of retinoblastoma [8]. far more children
are diagnosed each year with retinoblastoma in india (1,519) and
china (1,134) than in the countries with the next highest number of
incident cases (320 in each of indonesia and nigeria), estimated
from the birth rate, infant death rate, and population. of the 8,198
children newly diagnosed with retinoblastoma each year around the
world in countries with available economic data, only 8% are
fortunate enough to be born in the top 30 countries in terms of health
care expenditure. although quality of health care does not correlate
precisely with health expenditure, it is clear that 92% of the world’s
children with retinoblastoma have minimal access to optimal care.
based on anecdotal evidence, only 10% of children in the poorest
pediatr blood cancer doi 10.1002/pbc
fig. 2. a,b: the white tumor filling this child’s right eye is obvious on
a family’s digital image, months before the correct diagnosis of
retinoblastoma is made. c: the white pupil is featured in this t-shirt and
poster delivering in swahili an important public message: ‘‘a white
reflection in a child’s eye could be a sign of cancer! if your child’s eye
looks like the one in the photograph, make sure a medical doctor checks
both eyes. untreated, children’s eye cancer is fatal, but when diagnosed
early it is very curable! don’t be slow. help your child to be a survivor!’’.
[color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
1088 gallie et al.
parts of the world will survive retinoblastoma. registry data from
europe from 1988 to 1997 indicate significant variation in overall
survival, ranging from 83% in eastern europe to 97% in the british
isles and north europe [8]. however, our hope is that the
enthusiastic support of families of patients with retinoblastoma for
each other, their ongoing concern for the future children who will be
affected, and the ease with which they can communicate electronically
around the world, will change the dramatic discrepancies in
outcomes.
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