Literature Review To:

Monday, August 15
th
, 2005
TREATMENT OF INTRAOCULAR RETINOBLASTOMA
Primary Chemotherapy versus Primary External Beam Radiation Therapy
Combined With Adjunctive Therapies
FLORE!E M" MA#R#$
Consultants:
Lu%ongga & 'i%angunsong, M(
'etiowati 'uhard)ono, M(
Rita ' 'itorus, M(, *h(
(e+art%ent o, O+htha-%o-ogy
Fa.u-ty o, Medi.ine #niversitas /ndonesia
!i+to Mangun0usu%o 1os+ita-
2a0arta
2005
TABLE OF CONTENT

TABLE OF CONTENT.............................................................................................................2
LIST OF TABLES.....................................................................................................................2
LIST OF FIGURES....................................................................................................................2
REFERENCES
LIST OF TABLES
LIST OF FIGURES
CHAPTER I
INTRODUCTION
I.1. Background
Retnobastoma s a prmary magnant ntraocuar neopasm that arses from mmature
retnobasts wthn the deveopng retna. It s a neurobastc tumor and affects mosty
nfants and chdren.
1-2
Retnobastoma has been known as the most common prmary ntraocuar magnancy of
chdhood whch contrbutes 3 % of a chdhood magnances. The ncdence of ths
dsease wordwde s 1 n 15,000 to 1 n 34,000 ve brths.
1-5
Its annua ncdence s
hghest n the frst few months of fe; thereafter, the yeary ncdence decreases steady,
and s extremey ow by 6 years of age.
1
The medan age at the tme of dagnoss s
approxmatey 12 months n chdren wth batera retnobastoma and 24 months n
chdren wth unatera retnobastoma. Retnobastoma has equa dstrbuton between
boys and grs and has no known raca predecton.
1,4,5
Ths dsease appears to resut from oss or nactvaton of both norma aees of the
retnobastoma gene (13q14). The tmng of the oss or nactvaton of the two norma
2
aees determnes whether the dsease s germna or somatc.
1
Most chdren have the
sporadc form of retnobastoma. Commony, ths form affects unateray and ony a
snge tumor s present n the affected eye. In contrast, a sma number of patents have
a pror famy hstory of retnobastoma (germna form) and usuay, but not aways, have
mutpe tumors n both eyes. It has been stated that approxmatey 60-70 % of
retnobastoma cases are unatera whe 30-40 % are batera.
1,3,6,7
The management of ntraocuar retnobastoma s compex. If untreated, chdren
typcay de of ther dsease wthn 2-4 years of onset of symptoms. On the contrary, f a
retnobastoma patent s prompty treated, the chds fe coud be saved and may be
foowed by savage of the eye or vson. Medca therapy shoud be drected toward a
compete contro of the tumor and the preservaton of as much usefu vson as possbe.
Therapy s taored to each ndvdua case, consderng the overa stuaton, ncudng
the presence of metastatc dsease, rsks of second cancers, systemc status, ateraty of
the dsease, sze and ocaton of the tumors, and vsua prognoss. Other consderatons
are ocuar probems, the age, and genera heath of the chd. Severa optons are
avaabe for the treatment of ntraocuar retnobastoma.
1,8,9
Enuceaton s st commony used n seected cases and provdes the hghy certan cure,
but at the cost of compete vson oss n the nvoved eye. Actuay, f dagnosed eary, n
many cases of retnobastoma, t s st possbe to preserve the eye and savage vson
by usng other modates, such as externa beam radaton therapy (EBRT),
chemotherapy, paque radaton therapy, photocoaguaton, aser therapy, cryotherapy,
transpupary thermotherapy, and combned therapeutc modates.
1,8,9
One of the modates commony used to empoy regona eye-preservng method of
therapy for retnobastoma s EBRT. It has been the most mportant method of prmary
conservatve therapy snce 1903. EBRT treatment s hghy effectve aganst
retnobastoma, partcuary vsuay threatenng cases, but unfortunatey, compcatons
of radaton therapy are frequent and may threaten fe or sght. It accompanes
sgnfcant radaton-nduced compcatons, such as cataract, retnopathy, gaucoma,
vtreous hemorrhage, and cosmetc deformty, eventuay eadng to the oss of vson.
Partcuar concern of ths modaty s the potenton of second prmary magnances,
mosty n 40 % of patents wth RB assocated wth germ-ne mutaton.
8,9
Recenty, there has been a trend away from enuceaton and EBRT, and an ncrease n
the use of systemc chemotherapy as the prmary conservatve treatment. Prmary
systemc chemotherapy, whch s usuay combned wth foca treatment modates, has
been termed as chemoreducton. The concept of chemoreducton s to dever systemc
chemotherapy as the prmary treatment to reduce the sze or voume of the nta tumor
3
and ater to aow for more foca and ess damagng ntensve treatments, therefore, t
eradcate the resdua smaer tumor competey. It s stated that chemotherapy s beng
used ncreasngy and coud mprove the eye-preservaton rate by decreasng the tumor
sze and reduce the rsk of radaton-reated magnances. Nevertheess, systemc
chemotherapy s not exempt from compcatons, such as myeosuppresson.
1,2,8-11
I.2. Problem
The abrupt swtch from radaton to chemotherapy s st controversa, snce there has
never been a cnca comparson between radaton and chemotherapy, nor to ascertan
the optma parameters for chemotherapy. In ght of the frghtenng radaton rsks, the
urge to swtch to chemotherapy s understandabe and defensbe, but some scentsts
st use radaton as treatment of choce n seected cases, partcuary n chdren over
one year od on whom the radaton-nduced second cancer rsk s ow. The fed of
chemotherapy-based treatment of retnobastoma has progressed rapdy, but wth the
avaabty of modfed radaton devery technques, that may reduce second cancer
rsks, radaton s st n queston f t s actuay favor over chemotherapy. Whch of these
modates present the best resuts?
I.3. Purose
The ob|ectve of ths terature revew s to compare the outcomes of ntraocuar
retnobastoma management between prmary chemotherapy and prmary EBRT, each
combned wth ad|unctve therapes. These w be evauated by tumor reducton,
recurrence rate, and preservaton of the gobe as the effcacy factors, and compcatons
as a safety factor.
4
CHAPTER II
MATERIAL AND METHODS
The terature data reated to treatment of ntraocuar retnobastoma were coected
from MEDLINE and |ourna artces. The artces were taken from |ournas pubshed
between 1985-2005.
Incuson crtera were |ourna artces that reported treatment of ntraocuar
retnobastoma, usng ether prmary chemotherapy or prmary EBRT, each combned
wth ad|unctve therapes. Excuson crtera were |ourna artces that reported EBRT as
an ad|unctve therapy to prmary chemotherapy and chemotherapy tsef as an
ad|unctve therapy to prmary EBRT.
The data were dvded nto two groups whch were prmary chemotherapy wth
ad|unctve therapy data and prmary EBRT wth ad|unctve therapy data. Data are
presented n tabes. The data ncuded author, pubshed year and study desgn, tumor
stages of Reese-Esworth (R-E), number of tota retnobastoma cases n eyes, type and
protoco of prmary treatment, type of ad|unctve therapy, number of chemotherapy
cyces or tota radaton dose, foow up perod n months, and the effcacy factors whch
ncuded the percentage of tumor reducton rate, recurrence rate foowng compete
treatment, and the percentage of preservaton of the gobe. Other data were aso the
safety of each treatment whch conssted of the compcatons of each treatment.
Severa cassfcatons of retnobastoma have been deveoped to assst n the predcton
of the gobe savaton. The most popuar groupng s the Reese-Esworth cassfcaton (R-
E, see tabe 1) whch was used n a of the |ournas coected here. The retnobastoma
stages coud be dvded nto two groups; R-E group I-III whch are ow stage dsease and
R-E group IV-V whch are more advanced dsease. Not a of the teratures dvded the
patents nto these groups. Some of them descrbe the tota number of patents. Despte
ths ack of nformaton, these data were st ncuded for further evauaton of the
treatment outcomes.
Prmary treatment was defned as the nta treatment whch was chemotherapy or EBRT
foowed by ad|unctve therapes. It was apped ony n new patents that had not been
treated prevousy. Foowng the nta treatment, other foca treatments (ad|unctve
therapes) coud be apped to eradcate the resdua smaer tumor competey.
The protoco of prmary chemotherapy can be seen n tabe 2. It was usuay gven as
cycc chemotherapy every 3-4 weeks for up to 6 or more cyces and was combned wth
5
ad|unctve therapes. Not a of the teratures used the compete protoco whch s CVE
(Carbopatne-Vncrstne-Etoposde). Some of them used the parta protoco, such as CV
or CE, and sometmes t was combned wth other supportve agents, ke cycosporne A
(CSA). The regmen doses of the parta protoco were dfferent to the doses of the
compete protoco. If CE combnaton was apped, the doses were 150 mg/m
2
(5 mg/kg f
the weght of the patent s <10 kg) for etoposde and 200 mg/m
2
(6.7 mg/kg f the
weght of the patent s <10 kg) for carbopatne. If CV combnaton was apped, the dose
of carbopatne was 560 mg/m
2
and vncrstne was 0.05 mg/kg.
12-14
EBRT s a method of deverng whoe-eye rradaton. Protocos of EBRT were varous,
such as contact ens technque (CLT), reatve ens sparng (RLS) and modfed atera
beam (MLB).
15-16
CLT apped a drect atera or anteroatera beam usng a D-shaped
cone. Patents were frst mmobzed usng a customzed pastc mask n genera
anesthesa. The socentre was paced on the straght mb of the D-shaped fed at the
eve of the ora serrata. A soft contact ens attached to a rod wth a marker 7 mm from
the ens surface was apped to the affected eye. The D-shaped fed acheved coverage
of the target voume wth maxmum sparng of norma tssues (see fgure 1). The 50 %
sodose faen at the eve of the ora serrata, the 90 % sodose was 2-3 mm behnd ths
eve, and the ens and ptutary were covered by no greater than the 10 % sodose. By
means of the MLB technque, the anteror fed border was postoned 2-3 mm posteror
to the surgca mbus, so that the posteror poe of the ens was n the 50 % to 70 %
sodose ne and the eye was treated to the 90 % to 95 % sodose ne. The RLS tsef
treated the entre gobe wth coverage of the optc nerve to the conus. The radaton
doses to the mdde and posteror ens were smar to those wth MLB technques.
Standard target doses of radaton to the eye and orbt are usuay n the range of 40-50
Gy gven n dvded fractons of 150-200 cGy over 4-5 weeks.
The type of ad|unctve therapy was defned as the type of foca treatments used
foowng the prmary treatment. Ther functon was to support the nta treatment tsef,
thereby, reduced and controed the sze of the tumor. These coud ncude cryotherapy,
photocoaguaton, thermotherapy, and combnaton of these modates.
Foow up perod was defned as mean duraton of foow up of the patents unt the study
ended. These data were not correated wth the duraton of prmary treatment.
Tumor reducton rate was defned as percentage of eyes wth tumors that reduced
foowng the prmary treatment combned wth ad|unctve therapes. It coud be assessed
by ophthamoscope examnaton and by comparng sera vdeo mages, fundus drawngs,
and fundus photographs. Addtonay, the tumor voume rate, partcuary descrbed n
6
chapter IV, was dfferent from the tumor reducton rate. It was assessed by cacuatng
the radus, basa area, and heght vaues as determned by utrasonographc,
photographc, and physca examnaton, thereby, t showed the accurate measurement
of tumor reducton.
Recurrence rate was defned as percentage of eyes wth tumor that progressed after
competon of the prmary treatment combned wth ad|unctve therapes. The dsease
progresson coud be tumor growth, seed progresson, or new tumor formaton. These
tumors ater on were treated wth other foca therapes.
Fnay, preservaton of the gobe was defned as percentage of eyes whch coud be
savaged after competon of treatment as descrbed above and eyes whch st recurred
but ater were preserved by other addtona foca treatments.

Table 1. Reese!Ells"ort# class$%$cat$on %or $ntraocular ret$noblastoma
&rou I
'er( %a)orable
a3 'o-itary tu%or, 4 5 (( in si6e, at or 7ehind the e8uator
73 Mu-ti+-e tu%ors, none 9 5 (( in si6e, a-- at or 7ehind the
e8uator
&rou II
*a)orable
a3 'o-itary tu%or, 5:10 (( in si6e, at or 7ehind the e8uator
73 Mu-ti+-e tu%ors, 5:10 (( in si6e, 7ehind the e8uator
&rou III
+oubt%ul
a3 Any -esion anterior to the e8uator
73 'o-itary tu%ors 9 10 (( 7ehind the e8uator
&rou I'
,n%a)orable
a3 Mu-ti+-e tu%ors, so%e 9 10 ((
73 Any -esion e;tending anterior-y to the ora serrata
&rou '
'er( un%a)orable
7
Figure 1. Treatment set up for the contact lens
Technique
(adopted from ref no. 15)
a3 Massive tu%ors invo-ving over ha-, the retina
73 <itreous seeding
A77reviation: (( = dis. dia%eter
>Ado+ted ,ro% re, no" 1?3
Table 2. C#emoreduct$on reg$men and doses %or $ntraocular ret$noblastoma
+a( Carbolat$ne '$ncr$st$ne Etoos$de
0
1
- - -
-
Carbolat$ne
'$ncr$st$ne
Etoos$de
5@0 %gA%
2
1"5 %gA%
2
150 %gA%
2
1B"@ %gA0g ,or .hi-dren age 4 C@ %onths
0"05 %gA0g ,or .hi-dren age 4 C@ %onths and %a;
dose 4 2 %g
5 %gA0g ,or .hi-dren age 4C@ %onths
>This +roto.o- was a++roved 7y the !hi-drenDs 1os+ita- o, *hi-ade-+hia !o%%ittee ,or the
*rote.tion o, 1u%an 'u7)e.ts >!1* E 5B23" Ado+ted ,ro% re,eren.e no" 1B3
8
CHAPTER III
RESULTS
A tota of 17 |ourna artces was revewed and 11 |ourna artces met the ncuson
crtera. Eght studes reported the resuts of ntraocuar retnobastoma management
wth prmary chemotherapy combned wth ad|unctve therapes. Ony three studes
reported the outcomes of ntraocuar retnobastoma management wth prmary EBRT
combned wth ad|unctve therapes.
Tabes 3 and 4 show the summary of the effcacy and the safety factors of the reported
prmary chemotherapy wth ad|unctve therapy group, respectvey. We summarzed 5
reported studes usng compete protoco of chemotherapy wth or wthout CSA and 3
other studes whch ony apped parta protoco, ether CV or CE. These tabes were
subdvded n 3 subgroups whch are the coected studes usng compete protocos ony
n the advanced stages (2 artces), the studes usng compete protocos n a stages of
the tumors (3 artces) and the studes whch used parta protocos (3 artces). Tabes 5
and 6 show the effcacy and the safety factors of prmary EBRT wth ad|unctve therapy
group, respectvey. Most of the prmary EBRT groups reported the treatment outcomes
n the R-E group IV-V and ony one study reported the treatment resuts n R-E group I-III.
Yoo et al
19
used more ntensve chemotherapy as a proonged chemotherapy wth a
mnmum of 6 cyces. The frst 3 cyces of 3-week nterva chemotherapy were gven and
n cases where the tumor reduced sgnfcanty n sze after 3 cyces; ad|unctve therapes
were apped foowed by addtona 3 cyces of ad|uvant chemotherapy. In cases where
the tumor reducton was nsuffcent for ad|unctve therapes, a few cyces of the same
regmen of chemotherapy were added.
In ther study, Sussman et al
20
compared the tumor reducton between systemc
chemotherapy and EBRT n the treatment of advanced ntraocuar retnobastoma.
Twenty sx eyes were evauated whch were dvded nto two groups. Eghteen of 26 eyes
were treated wth chemotherapy and eght eyes were treated wth EBRT (see tabes 3
and 5).
Scott et al
16
nvestgated the outcomes between two technques of EBRT whch were RLS
and MLB.
9
Table 3. Efficacy factors of primary chemotherapy combined with adjunctive therapy group
No. Author ( published year) !"E stages Total !b #rotocol Type of adjunctive therapy Number $ean follow up Tumor reduction !eccurrence #reservation
%tudy design (eyes) of cycles ( months) rate ( & ) rate (& ) of globe (& )
1 Yoo et al
19
(2002) IIII () () () ()
!rospecti"e I## 5 100 0 $0
2 %ussman et al
20
(200&) IIII () 'iode laser( cr)otherap)( () () ()
*etrospecti"e I## 1$ com+ination 100 0 100
& ,allie et al
21
(199-) IIII 1. 100 0 100
!rospecti"e I## 12 $&.& 1-./ 92.$
. Friedman et al
22
(2000) IIII -- 0r)otherap)( photocoagulation(
!rospecti"e I## 9 thermotherap)
5 %hields et al
1$ 1 2&
(200.) IIII 51 100 12.5 9$
!rospecti"e I## 10/ 51 ./.5 &&.-
- 2e") et a l
12
(199$) IIII 15 100 1& 100
!rospecti"e I## 2& $/ 21 $/
/ 3ec4 et al
1&
(2000) IIII 1$ 100 5.55 100
!rospecti"e I## 15 $0 -0 /&.&
$ *odrigue5,alindo et al
1.
(200&) IIII 2. 0r)otherap)( photocoagulation( -2.5 $&.&
!rospecti"e I## 19 diode laser 2-.& 52.-
0#6 78 0%9
9++re"iation : 0#6; 0ar+oplatine"incristineetoposide( 0#; 0ar+oplatine"incristine( 06; 0ar+oplatineetoposide( 0%9; 0)closporine9( <9; <ot a"aila+le
/-
0#6 7 0%9
06
06
0#6 -
2/
1.
&1
0#6 Thermotherap)( cr)otherap)
/
2
0#6
0#
-
$
/
-
0r)otherap)( photocoagulation
'iode laser
0r)otherap)( photocoagulation
0r)otherap)( photocoagulation
&
2$
1&
5&.5
2. $5.&
1&
$
&5
Table '. %afety factors of primary chemotherapy combined with adjunctive therapy group
No. Author ( published year) !" E stages #rotocol (omplications
%tudy design
1 Yoo et al (2002) IIII 2eu4openia(
!rospecti"e I## throm+oc)topenia
2 %ussman et al (200&) IIII
*etrospecti"e I##
& ,allie et al (199-) IIII <eutropenia( anemia(
!rospecti"e I## throm+oc)topenia
. Friedman et al (2000) IIII 0)topenia( fe"er(
!rospecti"e I## neutropenia
5 %hields et al (200.) IIII
!rospecti"e I##
- 2e") et a l (199$) IIII <eutropenia( fe+ril(
!rospecti"e I## septicaemia
/ 3ec4 et al (2000) IIII <eutropenia(
!rospecti"e I## throm+oc)topenia
$ *odrigue5,alindo et al (200&) IIII =)elosuppression(
!rospecti"e I## fe+rile
#itreous hemorrhage
<9 0#6
06
06
0#
0#6
0#6 78 0%9
0#6 7 0%9
0#6
10
Table ). Efficacy factors for primary E*!T combined with adjunctive therapy
No. Author (published year) !" E stages Tot al !b #rot ocol
Type of adjunctive therapy
Total radiation dose $ean follow up Tumor reduction !eccurrence #reservation
%tudy design ( eyes) ( months) rate ( & ) rate ( & ) of globe ( & )
1 %cott et al
1/
(1999) IIII 10 <9 <9
*etrospecti"e I## 1- $1 $$
IIII 12 <9 <9
I## 20 51 $&
2 !hillips et al
12
(200&) IIII 2& $2.- $./ 91.&
*etrospecti"e I## 20 -5 .5 55
& %ussman et al
1-
(200&) IIII () 'iode laser( cr)otherap)( () () ()
*etrospecti"e I## $ com+ination 100 0 100
9++re"iation: *2%; *elati"e lens sparing( 02T; 0ontact lens technique( =23; =odified lateral +eam
.5 ,) at 1.$ ,)8fraction
&5
=2395 > isodose line
*2%95 >isodose line
.5 ,) at 1.$ ,)8fraction
&/
&/
0r)otherap)( photocoagulation
0r)otherap)( photocoagulation
<9
<9
2.
*2%95 >isodose line
02T 0r)otherap) .0 ,) at 2.5 ,)8fraction
.5 ,) at 1.$ ,)8fraction
Table +. %afety factors for primary E*!T combined with adjunctive therapy
No. Author ( published year) !"E stages #rotocol (omplications
%tudy design
1 %cott et al (1999) IIII =idfacial h)poplasia(
*etrospecti"e I## cataract
IIII =idfacial h)poplasia(
I## ptosis( retinopath)
2 !hillips et al (200&) IIII =idfacial h)poplasia(
*etrospecti"e I## sarcoma( cataract
& %ussman et al (200&) IIII =idfacial h)poplasia(
*etrospecti"e I## cataract
*2%95 >isodose line
=2395 >isodose line
02T
*2%95 >isodose line
11
CHAPTER I'
DISCUSSION
Eary dagnoss and prompt treatment of ntraocuar retnobastoma have contrbuted to
a marked mprovement n patent survva. Recenty, cnca advances have been
focused on ntraocuar tumor contro enabng ncreased gobe conservaton whe
mnmzng the rsk to the chd. Therefore, eary reducton n tumor sze s vta to the
successfu treatment of retnobastoma and aows for effectve appcaton of oca
treatments, consequenty eadng to tumor contro. Another consderaton s aso the
vsua compromse whch depends on the tumor sze and the extent of fovea
nvovement. For that reason, faster reducton n tumor voume and parta reducton n
fovea nvovement may aso aow mproved vsua acuty outcomes and decreased
ambyopa and strabsmus ncdence.
8,20
There are severa modates that have been used to decrease the tumor voume.
Hstorcay, prmary enuceaton and radotherapy were empoyed for advanced
retnobastoma. Other oca treatments coud cure smaer tumors wth few compcatons,
but were not suffcent management for extensve or dssemnated ntraocuar
retnobastoma and tumors whch are cose to the optc nerve or macua. These eyes
often receved EBRT. On the other hand, EBRT tsef s reated wth a 35 % of secondary
cancer (such as osteogenc sarcomas and rhabdomyosacomas) and a 90 % rsk of
cosmetc deformtes.
12,25-26
Durng ths tme EBRT technques have become more
sophstcated and dose-fractonaton schedues have been refned n an effort to
maxmze treatment and decreased the EBRT-reated compcatons. Thus, modern
radotherapy contnues to deveop n an attempt to mprove treatment accuracy and
mnmze ate radaton toxcty. In the 1990s, the use of chemoreducton started to be
encouraged as a ma|or roe n the nta management, even n advanced retnobastoma,
and fewer eyes requred prmary enuceaton or radotherapy.
9,13, ,22
The dscusson beow w be cassfed nto two parts. The frst part s the effcacy of the
prmary chemotherapy wth ad|unctve therapy group compared to the prmary EBRT
wth ad|unctve therapy group. The second part s the safety factors between these
modates.
A. T#e comar$son o% t#e e%%$cac( %actor
As shown n the tabe 3 and 5, both modates reduced the sze and voume of the
retnobastoma tumors, ether n ow or n advanced stages. The tumor reducton rates n
12
the prmary chemotherapy group showed a range of 62.5 % - 100 % n R-E group I-III and
26.3 % - 100 % n R-E group IV-V, whereas the tumor reducton rates n the prmary EBRT
group showed an 82.6 % rate n R-E group I-III, accordng to one study, and a range of 51
%- 100 % n R-E group IV-V. Thus, t can be concuded that the ow stages yeded hgher
tumor reducton rates than the advanced stages. Athough, t seems that the range of the
tumor reducton of prmary EBRT n R-E group IV-V was hgher compared wth prmary
chemotherapy, ths resut coud bear a bas due to the presence of one study wth CV
combnaton (Rodrquez-Gando) that yeded a ow outcome vaue. If ths study had been
excuded from the statstca anayses, the tota outcome of the prmary chemotherapy
woud have become sgnfcanty hgher than the tota outcome of the prmary EBRT.
As shown n tabe 3, the compete protoco wth or wthout CSA group showed a 100 %
tumor reducton rate n R-E group I-III and 51 % - 100 % n R-E group IV-V, whereas n the
parta protoco group showed a range of 62.5 % - 100 % tumor reducton n R-E group I-
III and 26.3 % - 87 % n R-E group IV-V. Consequenty, prmary chemoreducton, ether
usng compete or parta protoco, obvousy showed tumor reducton; however, R-E
group IV-V whch was treated wth parta protoco, especay, CV combnaton, yeded
poor responses.
Some |ournas reported exceent resuts of tumor reducton rates n R-E group IV-V n
whch advance dseases are usuay dffcut to treat competey (unfavorabe group) but
these were not found n these studes as reported by Sussman and Yoo. They dscosed a
100 % tumor reducton rate, no recurrence and a remarkabe percentage of tumor
voume reducton. Yoo treated the tumors wth more ntensve chemotherapy (ad|uvant
chemotherapy) but t s yet unknown whether more ntensve chemotherapy woud brng
out greater reducton n tumor voume as we as n tumor necross, whereas, Sussman
treated ther sub|ects n the prmary systemc chemotherapy group wth ad|unctve
transpupary dode aser therapy mmedatey before commencng systemc
chemotherapy whch may have nfuenced ther resuts. However, both of these studes
have demonstrated that prmary chemotherapy, partcuary wth compete regmens
combned wth ad|unctve therapes, mght yed a favorabe tumor reducton wth no
recurrence, even n advanced dseases. One of the studes of the prmary EBRT group
aso showed a remarkabe tumor reducton rate n R-E group IV-V, as reported by
Sussman. Athough the tumor reducton rate was 100 %, the sampng was mted n ths
study compared to the other EBRT studes. Sussman aso decared that prmary systemc
therapy patents treated wth prmary chemotherapy exhbted an earer reducton of
tumor voume than those wth EBRT. It s assumed that radotherapc effects mght not
be mmedatey apparent as ce death ntated through DNA damage often dd not
manfest unt competon of ce cyce.
20
13
Gae, Fredman and Sheds used compete regmens of chemotherapy as we as
Sussman and Yoo but n a stages of the retnobastoma cases. They aso found
ncreasng tumor reducton rates n amost a of ther patents, predomnanty wth
tumors n R-E grade I-III. However, they dd not report a 100 % tumor reducton n the
advanced stages unke the study of Sussman and Yoo. One of the compete protoco
studes that reported good resuts ether n ow and advanced stages s Gae et al.
Besdes the compete protoco combned wth ad|unctve therapes; they aso apped
hgh dose of CSA and ntensve foca therapes n ther protoco. They dscovered
dramatca tumor shrnkage mmedatey after 2 nta cyces of chemotherapy, even
vtreous seeds and extensve retna detachment dsappeared competey. Ther study
aso reported recovery of centra vson n ther patents, even wth paramacuar tumors
and macuar detachment. Gaes study seems successfu because of severa reasons.
Frst, t s possbe that the use of CSA reversed the chemoresstance retnobastoma;
consequenty enhancng the effcacy of chemotherapy tsef. The second reason s that
they consodated nta chemotherapy responses wth frequent foca therapy and
abated resdua or potentay actve tumor foc. The am was to destroy eary
reactvaton as soon as the tumors showed sgns of reactvaton (.e., an ncrease n
vascuarty or sze) and prevent the tumors from growng arger. Even though CSA
yeded a good resut, actuay the roe of CSA remans uncear.
21
The study of Fredman
and Sheds dd not appy CSA n ther protoco but they aso acheved good resuts;
however, ther resuts were not as hgh as Gaes, especay n R-E group IV-V. Sheds
even showed the owest tumor reducton rate n stage IV-V among the other studes of
compete protoco whch mght have been caused by the numerous advanced stages
whch most are unfavorabe. Consequenty, t can be concuded that the compete
protocos combned wth ad|unctve therapy and hgh dose CSA, mght contro the
retnobastoma tumor we and coud be used n a stages of the tumors, predomnanty
n the R-E groups IV-V, even n eyes wth the worst prognoss.
Addtonay, besdes the tumor reducton rate, some artces reported the sgnfcant
measurement of the tumor voume, both the thckness and the basene of the mass.
Sussman dscovered a 68 % voume reducton from basene of the tumors n patents
treated wth chemotherapy and 12 % reducton from basene n patents treated wth
EBRT. Yoo presented a medan 29.3 % (range 2.7- 76.6 %) decrease n tumor base and
75 % (range 21- 91.8 %) decrease n tumor thckness. Sheds aso measured the tumor
voume reducton and reported a 35 % mean reducton n basa dmenson and 49 %
mean reducton n thckness. There were no reports of tumor voume n the prmary EBRT
group.
14
Some of the coected |ourna artces used parta protoco of chemotherapy, such as
Levy, Beck, and Rodrguez-Gando. Athough, they presented tumor reducton n a
stages of the tumors, t seems that CE combnaton yeded a greater tumor reducton
rates than the CV. However, there was ony one study whch reported the outcomes of
CV. Levy et al and Beck et al used CE combnaton because of ther proven effcacy and
passage through bran-bood barrer. Both studed the effcacy of chemoreducton after 2-
3 cyces and yeded a smar favorabe response n each group of tumor, especay 100
% reducton rate n ow stages. If compared to the compete protoco group, parta
protoco, partcuary CE, acheved smar response such as compete protoco, especay
n the ow stages. The owest tumor reducton rate among a studes n tabe 3 s the
study of Rodrguez-Gando et al whch used CV combnaton. They dd not use etoposde
because of the concerns regardng etoposde-reated eukema. Besdes that, they aso
deayed the use of ad|unctve therapes unt dsease progresson. These ess ntensve
treatments mght nfuence ther poor resuts. However, they suggested treatment wth
CV couped wth aggressve foca therapes for patents that ncorporated etoposde.
14
It has been stated that these three-regmens (CVE) nfuenced the cyces of the tumor
ces, resutng n compete ce death. Each regmen has ts own specfc functon. The
more regmens apped to the tumor reducton, the more ce cyces may be affected,
thus, the faster the tumor reduces.
10,24-26
As shown n tabe 5, tumor treated wth prmary EBRT showed aso favorabe reducton
rates, smar to the prmary chemotherapy group. There was ony one study that
evauated the effcacy of prmary EBRT n a stages, whch was the study of Phps et al.
Ths study used the contact ens technque (CLT) and found a favorabe tumor reducton
rate n a stages, predomnanty stage I-III, but the resuts n the advanced stages were
ow. They found that the dsease of a stages coud st progress even though exposed to
radaton and ths was most found n advanced stage whch accompaned progresson of
vtreous seedng.
27
In contrast to Phps study, Sussman and Scott reported exceent
outcomes n stage IV-V usng RLS. Accordng Scotts study, t seems that tumor contro
was hgher n the RLS technque than that n the MLB technque. Ths mght have been
caused by a hgher frequency of anteror recurrences n the MLB group successfuy
treated.
It s dffcut to compare the recurrence rates between prmary chemotherapy wth
ad|unctve therapy group and prmary EBRT wth ad|unctve therapy group due to the
ack of nformaton wthn the EBRT group. As shown n tabe 4, the recurrence rate n the
prmary chemotherapy group ranged between 0 % - 53.5 % n R-E group I-III and 0 % -
15
60 % n R-E group IV-V rate. If treated wth compete protoco wth or wthout CSA, there
was no recurrence n stage I-III but there was a 0 % - 16.7 % recurrence rate n stage IV-
V. Tumors whch were treated wth parta protoco showed hgher recurrences whch
were 5.55 % - 13 % n stage I-III and 21% - 60 % n stage IV-V. The prmary EBRT study
aso showed hgh recurrence n the advanced stages, as reported by Phps et al. Thus, t
coud be concuded that tumors of a stages coud st recur but mosty n patents who
were treated wth parta protoco and patents n the R-E stage IV-V. The most prevaent
causes of the reported recurrence, ether prmary chemotherapy or prmary EBRT, were
tumor growth, vtreous seedng and persstent retna detachment.
Gae et al reported 16.7 % of ther patents of R-E group IV-V recurred. These tumors
showed a sma amount of foca reactvaton and vtreous seeds that arrested but
actuay never regressed, even though the patent was st undergong chemotherapy.
Ths was obvousy shown after chemotherapy had ended. Sheds even presented a
hgher recurrence rate among the compete protoco group partcuary n the advanced
cases (47.5 %). It was supported by Fredmans study
22
that dscovered that eyes wth
subretna and vtreous seeds pus subretna fud at the nta examnaton showed a
greater rsk of recurrence than patents wth tumor aone, thereby, eadng to treatment
faure owng to nadequate chemotherapy treatment. Ths was key shown n Sheds
study whch reported 34 % of cases wth retnobastoma seedng n the vtreous, 45 % of
cases wth subretna space, and 60 % of cases wth subretna fud on the nta vst.
Consequenty, a of these fndngs coud ead to a hgher recurrence rate. Meanwhe,
Fredman reported a 24 % faure of treatment due to recurrent vtreous seeds or tumor
growth. It was assumed that even though chemotherapy caused regresson of the man
tumor mass but t dd not effectvey treat the vtreous cavty. It s beeved that as the
tumors regressed durng the eary cyces of chemotherapy, the tumors fragmented and
reeased seeds n to the vtreous cavty, partcuary seen n group V tumors.
28
So, amost
a tumors n any stages coud recur; there s no guarantee that a treated ntraocuar
retnobastoma can competey arrested, thus, t s st mportant to contnue vgant
foow up n a retnobastoma patents even after competon of the treatment.
Athough Levy and Beck showed smar resuts of the tumor reducton rate but the
recurrence rates were dfferent. Ths mght be due to the onger foow up perod of Beck
where onger evauaton coud enabe detecton of recurrence. Beck reported that most
of the advanced stages have reapse patterns, such as massve vtreous seedng and
retna detachment. Addtonay, t s dffcut to compare the recurrence rate between CE
and CV combnaton because Rodrquez-Gando, the ony CV study, descrbed the whoe
16
resuts of the recurrence rate wthout cassfyng them n R-E group I-III and R-E group IV-
V.
The preservaton of the gobe rates seems smar between both modates. The
preservaton gobe rates n the prmary chemotherapy group range between 83.3 % -
100 % n stage I-III and 52.6 % - 100 % n stage IV-V whereas n the prmary EBRT group
showed 91.3 % n R-E group I-III, accordng to one study, and 55 % - 100 % n R-E group
IV-V. If treated wth compete protoco of chemotherapy the range of preservaton of the
gobe showed a remarkabe resuts - 100 % eyes coud be saved n ow stages and 80 % -
100 % n advanced stages whereas n parta protoco, the range was 83.3 % - 100 % n
ow stages and 52 % - 87 % n advanced stages. Hence, the preservaton of the gobe
rates was hgher n the ow stages than the advanced stages. The causes of enuceaton
of these reported studes were persstent retna detachment, dffuse vtreous or
subretna seedng, and subretna fud. It s not promsng that hgher tumor reducton
rate coud acheve a hgher preservaton of the gobe. Sussman and Yoo presented a 100
% tumor reducton rate but the preservaton of the gobe was hgher n Sussmans study.
The 100 % gobe preservaton rate n Sussmans study was key to be favorabe affected
by the use of ntensve ad|unctve therapy, thus the tumor contro was acheved.
Meanwhe, Yoo reported ony 80 % gobe preservaton rate due to the extensve retna
detachment. Gae presented remarkabe resuts n the tumor reducton rate and the
gobe preservaton rates whch mght be nfuenced by the use of CSA.
B. T#e comar$son o% t#e sa%et( %actors
Chemotherapy and EBRT s not exempt from compcatons. However there were no
treatment-reated mortates or serous fe-threatenng compcatons attrbutabe n
chemotherapy and a compcatons coud be managed we (reversbe).
29-30
The most
type of compcatons n the reported prmary chemotherapy group were bood dseases,
such as thrombocytopena, eucopena, neutropena, anema, vtreous hemorrhage, and
fever. There was no rena toxcty or ototoxcty. EBRT has sgnfcant mtatons
assocated wth severe compcatons, such as radaton-reated cataract, radaton
retnopathy, optc neuropathy and neovascuar gaucoma. Some of the EBRT
compcatons were reversbe, such as cataract. Cataract n these chdren may form for
at east 6 months after rradaton treatment and s often deayed for as much as 1-1.5
years after treatment. However, the most severe compcaton s orbta bone growth
arrest, whch resuts n cosmetc faca deformty (mdface hypopasa) partcuary n very
young chdren, as reported by Phps et al. It has been stated that the younger the chd
when EBRT s nstuted, the more dramatc the outcome. Pradhan stated that hgh dose
17
per fracton probaby contrbuted to the ncreased compcatons, but t was not found n
the coected teratures.
29-32
Though t s cear that EBRT ncreases the rsk of secondary cancers n radaton, the
nducton effect of chemotoxc agents on secondary cancers st remans uncear. The
drugs used n the chemoreducton protoco, such as CVE, have been used extensvey
and there has been concern about the potenta deveopment of secondary magnant
neopasm that mght be nduced by chemoreducton, such etoposde or tenposde
treatment regmens. Ths regmen may nduce secondary acute myeobastc eukema
(AML). Fortunatey, the ncdence of secondary AML after etoposde treatment was not
nordnatey hgh (0.7 % at 6 years).
13
Addtonay, to evauate f ad|unctve therapes coud gve better resuts n supportng
the nta treatment tsef, artces whch addressed prmary chemotherapy aone,
wthout appyng any ad|unctve therapes were aso coected and revewed. There were
few studes whch ony used prmary chemotherapy as nta treatment. These studes
showed that chemotherapy aone reduced retnobastoma tumors but wth ower
percentage outcomes than the chemotherapy combned wth ad|unctve therapy group.
33-
34
The tumor reducton rates were ower and the recurrence rate was very hgh n ths
protoco, such as reported by Wson et al
32
,

83.3 % n group I-III and 100 % n group IV-V.
Wthout ad|unctve therapy, there was no 100 % preservaton of the gobe rate, as was
seen n the prmary chemotherapy wth ad|unctve therapy studes. However, there were
reversbe compcatons such as myeosuppreson. Thus, t coud be concuded that
mutagent chemotherapy aone does not ensure ntraocuar retnobastoma contro.
Moreover, further foca therapy s needed and s a crtca part of the chemotherapy
protocos. Murphree
35
stated that appcaton of oca ad|unctve therapes at the tme of
systemc chemotherapy ncreases the effcacy of the chemoreductve agents whch
aows for reducton n tota radaton dose and mantan exceent oca tumor contro.
Ths terature revew has aso mtatons. As presented n the tabes, most of the
coected studes are dffcut to be compared. There were varatons n the number of
cases, the protoco and cyces of prmary treatment, the type of ad|unctve therapy, and
the foow up duraton. Despte these unequa data, we coud st obtan some mportant
nformaton; that s the rate of tumor reducton, the rate of recurrence and the type of
compcatons, and aso the rate of preservaton of the gobe. A of ths nformaton mght
hep us to choose whch of these treatments coud acheve better outcomes n treatng
ntraocuar retnobastoma.
18
Figur 2. R!i"#$%&'!#(& !u(#r' $)#r &"* &)!r +,(#!,r&-. /i!, +.+%#'-#ri" !,r&-. &"* )#+&% !,r&-..
19
CHAPTER '
CONCLUSION
Both modates, ether prmary chemotherapy or prmary EBRT combned wth ad|unctve
therapy, showed reducton of the tumors, ether n ow or advanced stages. However, the
ow stages yeded hgher tumor reducton rates than the advanced stages. It seems that
ow stages mght better treat wth prmary chemotherapy whe advanced stages wth
prmary EBRT.
Even though the tumor reducton rates were exceent, a stages of the tumors st mght
recur. Thus, there s no guarantee that the dsease w arrested even after competon of
treatment. However, the recurrence rates were mosty found n the R-E stage IV-V than
the R-E stage I-III.
The preservaton of the gobe rates seems smar between both modates. The tumors
n the ow stages coud be preserved better than the advanced stages. There was no
certanty that hgher tumor reducton rate coud acheve hgher gobe preservaton rate.
Athough both treatments showed good resuts, the dverse compcatons emerged from
the treatments must be consdered. Systemc chemotherapy appears to be ess key to
resut n sgnfcant oca adverse effects than treatment wth EBRT.
SUGGESTIONS
Further mutcentre, arge numbers of patents and randomzed tras wth onger foow
up are needed to evauate the best drug combnaton and the best duraton of appyng
prmary chemotherapy whch woud brng out greater reducton n tumor voume. Other
consderatons to be studed are the treatment faure reated to drug resstance, ong
term foow-up, and the best treatment for advanced ntraocuar retnobastoma.

20
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22