Management of Pediatric Malignancies - ASTRO...management of Hodgkmanagement of Hodgk tumor and...
Transcript of Management of Pediatric Malignancies - ASTRO...management of Hodgkmanagement of Hodgk tumor and...
Management of Ped
Suzanne L. WM i l Sl KMemorial Sloan-Kette
diatric Malignancies
Wolden, MDi C Cering Cancer Center
Disclo
• I have no conflicts of in
osure
nterest to disclose.
Learning O
• Define the current stanpediatric brain tumors p
• Describe the controvemanagement of Hodgkmanagement of Hodgktumor and neuroblasto
• Interpret the risks and• Interpret the risks and radiotherapy in the treretinoblastomaretinoblastoma.
Objectives
ndard of care for and sarcomas.rsies in the kin lymphoma Wilmskin lymphoma, Wilms oma.benefits ofbenefits of atment of
Distribution of comalign
Soft Leukemia31%
OtherEye3%
Bone5%
Other7%
ommon pediatric pancies
Tissue6%
Wilms' Tumor6%L hLymphoma
14%
Neuroblastoma7%
Germ Cell3%
Central Nervous Systemy
18%
Pediatric Canc
607080
405060
102030
010
All cancers Bone sarcom
cer Cure Rates
1960s
1990s
mas Soft tissuesarcomas
Medullob
• 10-20% of pediatric b• ~300 patients diagnos300 patients diagnos• Peak incidence 5 to 7
2 1 l t f l• 2:1 male-to-female ra• Usually arises in midl
and grows anteriorly i
blastoma
brain tumorssed annually in U Ssed annually in U.S.
7 yearstiatioine of cerebellar vermis into 4th ventricle
MedulloblastoMedulloblastooma pathologyoma pathology
• Classic• Large cell anaplasticg p• Desmoplastic nodular
MolecularMolecular
•
•
Sc
r geneticsr genetics
SHH activationSHH activation• Cerebellar hemisphere
DN & LCA hi t l• DN & LCA histology• Infants
WNT mutations• Dorsal brainstemDorsal brainstem• Classic histology
chwalbe et al. Clin Can Res 2011;17:1883Gibson et al. Nature 2010; 468:1095
Presen
• Vomiting (67%), headaataxia (40%) and nauataxia (40%), and nau
• 80% have hydrocephaof 4th ventricleof 4th ventricle
• 30% disseminated dis(i id hi h i h(incidence higher in chusually involves spina
ntation
ache (60%), usea (39%)usea (39%)alus due to obstruction
ease at diagnosis hild 3 )hildren < 3 years); l subarachnoid space
MedulloblastoMedulloblasto
• MRI with contrast of e• Lumbar puncture
oma work-upoma work up
ntire neural axis
StStag
• Chang “M” stage• 0: no dissemination• 1: positive cytology• 2: intracranial nodules• 3: spinal nodules • 4: extra-neural disease4: extra neural disease
iging
Average risk: • age > 3 years• < 1.5 cm2 residual• M0 stage
High risk:• age < 3 years• > 1.5 cm2 residual
M t• M+ stage
Old standard:Old standard:
• 36 Gy craniospinal + poste• 36 Gy craniospinal + poste
• 5 year EFS for standard ris• 5 year EFS for standard risalone or RT + non-cisplatin
• Survivors have high risk ofgrowth, neurocognitive, en
• Risk highly correlated to pa
surgery + RTsurgery + RT
erior fossa boost to 55 8 Gyerior fossa boost to 55.8 Gy
sk patients treated with RTsk patients treated with RT n chemotherapy ~ 60%
f late effects due to RT: ndocrine, 2nd cancers
atient age and RT dose
Can you decreCan you decreCCG
• 1986-90, 81 average • 23.4 Gy vs 36 Gy CSI• closed early due to re• closed early due to re• 5-year EFS 67% vs 52
ase CSI dose?ase CSI dose? G-923
risk patientsI alonelapses in 23 4 Gy armlapses in 23.4 Gy arm2% (P=0.08)
Thomas et al. JCO 2000;18:3004
Packer regimen:Packer regimen:
• 1983-93, 63 patients a• Sub-total resection (19(
and/or M-1+(15)• CSI (36 Gy 23 4 Gy ifCSI (36 Gy, 23.4 Gy if • Add vincristine, cisplat
5 PFS 83% (M 0 90• 5 yr PFS 83% (M-0 90
Pa
: single arm trial: single arm trial
ge 2-219), brainstem inv (42), ), ( ),
< 5 years) + PF boost< 5 years) + PF boostin, lomustine% M 1 67%)% vs M-1+ 67%)
acker et al. J Neurosurg 1994;81:690
CCG 9961 pCCG-9961 p
379 patients 3 21 yo <• 379 patients 3-21 yo, <• 23.4 Gy CSI + PF boos• Weekly vincristine, the• Randomized: vincristin
vincristine-cisplatin-cyc• No difference in chemoNo difference in chemo• 5 year EFS = 81%, sur
hase III trialhase III trial
< 1 5 cm2 M 0< 1.5 cm2, M-0st to 55.8 Gyn:e-cisplatin-lomustine vs p
clophosphamideo regimenso regimensrvival = 86%
Packer et al. JCO 2006;24:4202
Current stanCurrent stan
Surgery
< 3 yo
g y
Average• M0, a
• < 1 5 cm2 r• < 1.5 cm r
High dose CT 23.4/55.8 CS
50% EFS 80% E~ 50% EFS ~ 80% E
ndard of carendard of care
> 3 yo
e-riskndresidual
High-risk• M+, or
• ≥ 1 5 cm2 residualresidual • ≥ 1.5 cm residual
36/55.8 CSI + CTSI + CT
EFS ~ 65% EFSEFS ~ 65% EFS
C dCan we reduce
Severe ototoxicity 25 50Severe ototoxicity 25-50
• 32 consecutive MKSCC p32 consecutive MKSCC p• Boost to tumor bed plus 1• 28 received chemotherap• 28 received chemotherap• 20 treated with 3D RT, 12• 5 year EFS 84%• 5 year EFS 84%• One isolated PF failure o
b t l ?boost volume?
0% due to cisplatin + RT0% due to cisplatin + RT
patients (5 high risk)patients (5 high risk)1.5 cm marginpypy2 with IMRT
utside boost field
Wolden et al. JCO 2003;21:3079
Whole t iposterior
fossa
Tumor bed
Normal tiss
Lateral field
Normal tiss
Lateral field
posterio
Planning target volume 102g g
Cochlea 104
Temporal lobes 84%
Parotid glands 71%
Pituitary & hypothalamus 35%
sue sparing
ds treating Conformal therapy
sue sparing
ds treating
or fossa
Conformal therapy
treating tumor bed
2% 105%
4% 43%
% 48%
% 10%
% 9%
Boost tec
2D 3
chniques
3D IMRT
Dose volume histoDose volume histoogram for cochleaogram for cochlea
IMRT2D3D
ProtonProton therapytherapy
IMRT UIMRT U• 33 consecutive patientsp
Standard-risk 23.4 Gy CSI w/ boost toIT 131I-3F8 18 Gy CSI wIT I 3F8, 18 Gy CSI wHigh-risk 36 or 39.6 Gy CSI w/ bo
• Concurrent vincristine, cisplatin-based chemot
• Pre- and post-treatmen31 patients
Pol
UpdateUpdates
o 55.8 Gy, orw/ boost to 54 Gyw/ boost to 54 Gy
oost to 55.8 Gy
then standardtherapynt audiograms available for
kinghorn et al. IJROBP 2011;81:e15
Patterns oPatterns o
• Posterior fossa failure w• Posterior fossa failure w
• Distant failure n=2• Distant failure, n=2
• Combined PF and distaCombined PF and dista
No isolated posterior foNo isolated posterior foboost volume
of Failureof Failure
w/in boost field n=2w/in boost field, n=2
nt failure, n=3nt failure, n 3
ossa failures outside of theossa failures outside of the
Cochlear DCochlear D
Cohort Group
Standard Risk (18.0/54.0 Gy)
Standard Risk (23.4/55.8 Gy)
High Risk (36 or 39.6/5580 Gy)
DosimetryDosimetry
Mean dose (Gy) SD
38.6 ± 3.1
40.6 ± 4.7
49.1 ± 4.6
OtotoOtotoat
ients
ber
of Pa
Num
b
10
Grade (CT
oxicityoxicity
Grade 3: 6 %Grade 4: 0
Median f/u: 19 mo
0
3 42
TCAE v3.0)
Current COG Studyy: Average Risk MB
CNS germ c
• In West, 3-11% of ped– Higher incidence in Japg e c de ce Jap
• Most common in 2nd -3M l f l i 2 1• Male : female ratio 2:1
• Primary sites: Pineal ay– 5-10% of GCT prese
cell tumors
iatric brain tumorspan and Far East pa a d a ast
3rd decade of life
and suprasellar regionp gent in both sites
Pineal germinoma
Suprasellar nonSuprasellar nonn-germinoma GCTn germinoma GCT
Classification of
• Germinoma• Embryonal carcinoma• Yolk sac tumor• Choriocarcinoma• Teratoma
– ImmatureImmature– Mature
• Mixed Germ CellMixed Germ Cell
Intracranial GCT
most common: 2/3 of cases
N i GCTNon-germinoma GCT1/3 of cases
Diagnog
Parinaud’s syndrome, diabetes i i id l t d ICPinsipidus, elevated ICP
Historically, patients received y pempirical trial of radiotherapy
Modern techniques now allowModern techniques now allow safe biopsy
MRI brain + spine; CSF cytologyMRI brain + spine; CSF cytology
Tumor markers: serum & CSF
osis
Packer et al. Oncologist, 2000; 5312.
Parinaud S
• Paralysis of upward gaze
• Convergence nystagmus• Convergence nystagmus
• Light-near pupil dissociation
• Lid retraction (Collier’s sign)
Syndrome
Management of CManagement of C
Radiation alone is gold sta• Radiation alone is gold-sta• 5-yr PFS 85-95%; OS 90-98%• CSI not necessary for isolated d• CSI not necessary for isolated d• Whole ventricle prophylaxis is!• High dose chemotherapy: 50% g py %• No clear role for chemotherapy• Recommendation:
– 25 Gy whole ventricle (CSI i– 45 Gy to gross disease
Haa
CNS GerminomaCNS Germinoma
ndardndard
diseasedisease
fail
f CSF+)
as-Kogan et al. IJROBP, 2003; 56(2)511.
Nongerminoma g
• Poor prognosis: 5 year PF
R i i t i h th• Require intensive chemoth– Local failure common: secon
• RT fields controversial: CS– Pattern of failure same as ge
COG t l ACNS0122 3– COG protocol ACNS0122: 3
germ cell tumors
FS 50-60%; OS 60-70%
d RTerapy, surgery and RTnd look surgery recommended
SI versus whole ventricleerminoma: favors whole ventricle36 G CSI b t t 54 G36 Gy CSI, boost to 54 Gy
Craniopha
• 6-9% of pediatric brain tu• Benign, arises from phar• Presentation:
– Short stature, hydrocepha• Best treatment: subtotal
– Results in control rate of 7– Total resection associated
and equivalent control rate– May treat post-operative GMay treat post operative G
aryngioma
umors, peak age 10ryngeal cell rests
alus, vision loss, not DIresection + 54 Gy
75-80%d with increased late morbidity esGTV + marginGTV + margin
Craniopharyngioma
Common pedia
– Rhabdomyosarcom– Non-rhabdo soft tissNon rhabdo soft tiss
• Synovial most common
– Ewing sarcoma– Ewing sarcoma– Osteosarcoma– Desmoplastic small
atric sarcomas
masue sarcomassue sarcomas
round cell tumor
Rh bdRhabdomy• The most radiosensitiv• 350 cases annually in
– Two-thirds of cases are• Majority of patients rec
yosarcomave sarcomathe U.S
e in children under age 7gceive RT
RMS: molecRMS: molecGeneChim
t(2;13)(q35;q14)
Chim
PAX3 FKHR
Chromosome 2
(or pax7 chr 1)
Chromosome 13
• Embryonal tumors may have LO
Mao et
cular biologycular biologye Fusions with Novel
meric Protein Products
Activation of
meric Protein Products
Activation of aberrant gene program
Malignant transformation
Scrable et al Nat re 329 645 1987
OH at 11p15, encodes for IGF II
Scrable et al. Nature 329:645, 1987t al. Proc Natl Acad Sci USA 91:9871, 1994
Distribution bDistribution by primary sitey primary site
Head and Neck (10%)Head and Neck (10%) Parameningeal (16%)Genitourinary (24%)
Extremities (19%)
Other (22%)( )
Orbit (9%)
RMS: Pattern
• Distant metastases, < – lungs, bone marrow, alungs, bone marrow, a
• Regional lymph nodes• Regional lymph nodes– 0-1% for orbit
30% for paratesticular– 30% for paratesticular
ns of spread
¼ at presentationnd bonend bone
s varies by sites varies by site
and extremityand extremity
Lawrence et al. Cancer 60:910, 1987
IRSG tIRSG post-sur
• Group I Localized resecte
• Group II Positive mor resec
• Group III Gross res
• Group IV Distant me
i l irgical grouping
disease, completely edmicroscopic margins cted regional diseaseg
idual disease
etastases
RMS: pretreatRMS: pretreatStage Sites
1 Orbit, H/N (not PM), GU(not B/P)
2 B/P, Extremity, PM,Othe
3 B/P, Extremity, PM,Othe
4 Any4 Any
tment stagingtment stagingSize Metastases
all N0 or N1
r <5cm N0
r <5cm N1>5cm N0 or N1
any M1any M1
Survival by tSurvival by t
80%
60%70%80%
40%50%
%
20%30%
0%
0%10%
1960's IRS-I IR
treatment eratreatment era
RS-II IRS-III IRS-IV
IRS IV (19IRS IV (19
• Radiation Guidelines:– Dose:
• Group I, Stage 1/2: no R• Group III randomized to
(1.1 Gy BID)– Volume: GTV + 2cm– Timing: Day 0 PM with
ICE. Week 12 for othe
991-1997)991-1997)
RT. Group I, Stage 3 / II: 41.4 Gyo 50.4 Gy CRT vs 59.4 Gy HRT
C OSh CN palsy, BOS erosion, ers
Failure-free survlocal/regiona
by chemothy
0.80.91.0
viva
l
0 50.60.70.8
free
Sur
v
0 20.30.40.5
Failu
re-f
Log Rank Test: p=0.520.00.10.2
0 1 2 3Yea
0 1 2 3
ival of patients with l RMS on IRS-IV erapy regimenpy g
VIEVACVAI
VIE
4 5 6ars
4 5 6
Failure-free survival oIII t b dIII tumors by rad
1.0
0 70.80.91.0
Surv
ival
0.50.60.7
re-fr
ee S
0 20.30.4
Failu
Log Rank Test: p=0.760.00.10.2
0 1 2
Ye
0 1 2
of patients with Group di ti h d ldiation schedule
Conventional
Hyperfractionated
3 4 5
ears
3 4 5
Failure-free survivaa u e ee su atumors by p
0 80.91.0
al
E0 50.60.70.8
e Su
rviv
a
0.20.30.40.5
lure
-free
Log Rank Test: p<0.0010.00.10.2
0 1 2 3
Fai
Years
al for local/regional a o oca / eg o aprimary site
GU non-B/P H & N
Orbit
Extremity
GU B/PH & N
Other PM
4 5 6s
IRS IV (19IRS IV (19
• 5-yr local control for– Extremity 9y– Orbit 9– Bladder/prostate 9Bladder/prostate 9– Head and neck 8– Parameningeal 8Parameningeal 8– Other 9
D
991-1997)991-1997)
r Group III RMS6% 5%0%0%8%4%4%0%.
Crist et al. JCO 19:3091, 2001Donaldson et al. IJROBP 51:718, 2001
IRS V (19
E i t l d d• Experimental dose redu– Group I alveolar/undiffer– Group II N0: 36 Gy– Group III orbit/eyelid: 45 – Group III second look su
• negative margins: 36 Gy• microscopically + margins
– Group III requiring 50.4: GTV + 5 t 36 G ifGTV + 5 mm at 36 Gy if
999-2004)
tiuctions:rentiated 36 Gy
Gyurgery
s: 41.4 Gyvolume reduction to initial N0 d t 41 4 G if N+N0, and at 41.4 Gy if N+
COG Int risk: ARSCOG Int risk: ARS
• Randomized VAC vs VA• Early radiotherapy for a
– attempt to improve loca– allow radiotherapy devia
• Concurrent Irinotecan w– potential for radiosensiti– pilot data from ongoing
• PET scans for staging a
ST0531 (ongoing)ST0531 (ongoing)
AC / V + Irinotecanll patients at week 4l & possibly distant controlation for infants < 2 years
with radiotherapyizationMSKCC trial
and response evaluation
COG ARST0531COG ARST0531EV
Week 0 1 2 3 4 5 6Week 0 1 2 3 4 5 6V V V V V V VV V V V V V V
VAL
V V V V V V VV V V V V V VI I II I II I
Radiot
EVAL
Week 12 13 14 15 16 1Week 12 13 14 15 16 1V V V V AA AAC C CC
: V/CPT-11 arm:: V/CPT 11 arm:
6 7 8 9 10 116 7 8 9 10 11V V V V V VV V V V V VV V V V V VV V V V V VI I I I CC
therapyEVAL
17 18 19 20 21 22 23 17 18 19 20 21 22 23 V V V V V V V VV V V VI II I AA
CC
Dose accordiGroup
Dose accordi
I Localized disease, cresected with negat
II Positive microscopresected regional d
III Gross residual dise
IV Distant metastases
ing to GroupDose (Gy)
ing to Group
completely tive margins
36
ic margins or isease
36 (N0) 41.4 (N+)
ease 50.4
As above
SIOP Experie
• 503 nonmetastatic RMS• Goal to avoid radiothera• Variety of 1st and 2nd lin• OS = 71%• OS = 71% • EFS 57%• 49% cured without sign
ence: MMT 89
S patients treated 1989-95apypye chemotherapy regimens
ificant local therapy
Stevens et al. JCO 23:2618, 2005
MMT 89 vMMT 89MMT 89
5 year % ratOS EF
Total 71 5Alveolar 38 2Embryonal 78 6
Orbit 85 5Orbit 85 5H&N 64 3Extremity 46 3y
vs. IRS IVIRS IV
teIRS IV
5 year % rateFS OS EFS57 84 7827 71 6463 87 82
53 100 9353 100 9335 89 8335 71 64
Donaldson et al. JCO 23:2586, 2005
FDG-PET scFDG-PET scMSKCC ex
• All primary tumors PET – SUV 4.0 - 12.7
• For all sites:– sensitivity 81% y– specificity 97%
• Therapy altered in 14% py– LN + detected only on P
K
can stagingcan stagingxperiencepositive
casesET
lem, Wolden et al. J Ped Hem Onc 2007
Pre-treatmennt PET scan
Local ControlLocal Control by Pre RT PETby Pre-RT PET
L l C t l b FLocal Control by FFi t P t RT PETFirst Post-RT PET
Infratemporal fossaInfratemporal fossaa with PM extensiona with PM extension
ParameningeC i (IMComparison (IM
(Kozak, Yoc
Results:• Improved dose conformal
tissues examined excepttissues examined except as the parotid and cochle
% Dose1051001008060404020
al RMS: Dose MRT P t )MRT v Protons)ck, IJROBP)
lity of protons spared most normal for a few ipsilateral structures suchfor a few ipsilateral structures such a.
Interstitial tongueInterstitial tonguee brachytherapye brachytherapy
Electron forElectron forr eyelid RMSr eyelid RMS
Non-rhabdo soft (NRSTS) are m
children and
61%550-600 cases/yr
tissue sarcomas ore common in adolescents
/39%
~350 cases/yr
RMSNRSTS
SEER Program 1975-1995, NCI
NRSTS predominateNRSTS predominateage gr
89
10
ers
45678
All
Can
ce
1234
% o
f A
0< 5 Years 5-9 Years 1
Age Gr
es in older pediatrices in older pediatric roups
RMSNRSTSTotal
0-14 Years 15-19 Years
roup
SEER Program 1975-1995, NCI
COG ARST0032 lCOG ARST0032: l
D fi i iDefinitive surg
Clinical Group I
No RT
l d NRSTSlow grade NRSTS
i l igical resection
Clinical Group II
Would local recurrenceresult in significant
bidit ?morbidity?yesno
No RT RT 55.8 Gy
COG ARST0032: hCOG ARST0032: h
Definitive surgDefinitive surg
Tumor < 5cmTumor < 5cm
Margins ≥ 1 cm orunbroken fascial plane?
No RT RT 55 8 Gy
noyes
No RT RT 55.8 Gy
high grade NRSTShigh grade NRSTS
gical resectiongical resection
Tumor > 5cmTumor > 5cm
RT 55 8 Gy +RT 55.8 Gy +Ifos/Doxo x5
Ewing sarcoma fEwing sarcoma f
300 cases per ear in U• 300 cases per year in U.– Most common in second d
Arises from bone or soft ti– Arises from bone or soft ti– Classic EWS-FLI1, t(11;2– Extremely rare in childreny
• Relatively radiosensitive • Role of RT not as well stRole of RT not as well st• Patients may have surge
family of tumorsfamily of tumors
SS.decade (10-20 years)issueissue22)n of African or Chinese ethnicityy
tudied as in RMStudied as in RMSery, RT or a combination
Radiation therapy fRadiation therapy fMSKCC resul
• 60 patients received p– 31 RT alone31 RT alone– 26 Post-op RT– 3 Pre-op RT3 Pre op RT
• All had VACIE (EFT chM di 16 (2 40)• Median age 16 (2-40)
• Median follow-up 41 m
for Ewing sarcomafor Ewing sarcoma lts 1990-2004
primary site RT
hemotherapy regimen)years
months
La, Wolden et al. IJROBP 64:544, 2006
Local control: localized
100
Local control: localized
70
80
90
50
60
70
roba
bilit
y
20
30
40Pr
0
10
0 2 4
vs metastatic diseasevs. metastatic disease
Localized
6 8 10
Metastatic
p = 0.036
Years
Di f
100
Disease free surv
80
90
100
50
60
70
babi
lity
20
30
40Prob
0
10
20
0 2 4
Y
i l b t ivival by tumor size
< 8 cm
>/= 8 cm
p < 0.001
6 8 10
Years
Survival with localized
100
Survival with localized
70
80
90
50
60
roba
bilit
y
20
30
40Pr
0
10
0 2 4YY
d vs metastatic diseased vs. metastatic disease
Localized
6 8 10Y
Metastatic
p < 0.001
Years
Intergroup EwingIntergroup Ewing(IES
• Three options for loca– Surgery alone if margi– Surgery alone if margi– 45-50.4 Gy post-op if m
55 8 Gy definitive RT– 55.8 Gy definitive RT • Margins have decrease
bundle to 5cm and now
• Local failure is approx
sarcoma studies sarcoma studies SS)
al control:ins negativeins negativemargins are <5mm
ed from whole bone or muscle w to 2 cm
ximately 10%
Local progressionsarcoma by surgsarcoma by surg
n in pelvic Ewing gery RT or bothgery, RT, or both
Yock et al, JCO 24:3838, 2006
Event free survivasarcoma by surgsarcoma by surg
al in pelvic Ewing gery RT or bothgery, RT, or both
Yock et al, JCO 24:3838, 2006
Cooperative Ewinp(CESS 81, 86
• Local control best with surgery >90%
• RT local control 74% ailu
re%
– NEGATIVELY SELECTED!fa
• Equivalent EFS, OS
ng sarcoma study g y6, EICESS 92)
40
303540
distant
152025
ailu
re % both
l l
51015fa local
0RT S S +
RT
Schuck et al, IJROBP 55:168, 2003
RT
Ewing SaAskin Tumor + W
arcoma: Whole Lung IMRT
Osteosa
• Relatively radioresista
• RT for unresectable os56% i d t– 56% received protons
– 5 year LC = 78% after 5 LC 40% ft– 5 year LC = 40% after
DeDe
arcoma
ant: requires high dose
steosarcoma at MGHith d t 80 Gwith doses up to 80 Gy
incomplete resectionbi lbiopsy only
eLane et al IJROBP 61(2) 492 2005eLaney et al. IJROBP 61(2):492, 2005
Desmoplastic smaDesmoplastic sma(DSR
• Aggressive abdominal tu• Peritoneal seeding simiPeritoneal seeding, simi
ll round cell tumorll round cell tumor RCT)
umor in young menlar to ovarian cancerlar to ovarian cancer
DSRCT H
H & E
HistologyVimentinVimentin
CytokeratinCytokeratin
Desmin
Molecular
• Specific recurrent chromosomal abnormality
• t(11;22)(p13;q12)
• Translocation of 2 genes gassociated with other malignancies
r Genetics
y 131211
p15
CHR 22
11
12
13
q
14
131211
1112
p
WAGR EWINGS SARCOMATRANSLOCATION
EWSWT1
CHR 2213
142122
23
q
2425
CHR 11
Multimodality Try
I t i P6 h th• Intensive P6 chemothera• Maximal surgical debulk• +/- Stem cell transplant• WAPRT: 30Gy in 1.5Gy
• 20 patients 1992-200020 patients 1992 2000• Median age 17; 95% ma
G
reatment Results
apyking
fractions
ale
Goodman, Wolden, et al. IJROBP 2002
Disease Fre100
80
100
M
60
rcen
t
20
40Pe
00 12 24 36 480 12 24 36 48
M
ee Survival
4-year DFS = 14%edian time to relapse = 21 mos
8 60 72 84 96 1088 60 72 84 96 108
onths
Whole abdomenWhole abdomenn-pelvis IMRTn pelvis IMRT
Pediatric sarcomPediatric sarcom
• Radiation plays a critica• Radiation plays a criticawith preservation of form
• Future challenges for ra• Future challenges for ra– further improvement in l– reduction of late-effectsreduction of late-effects– prevent nodal and dista
• Radiation therapy must• Radiation therapy must – new technologies promi
ma conclusionsma conclusions
al role: maximize cureal role: maximize cure m and functionadiation oncologyadiation oncologylocal control
nt metastasesbe individualizedbe individualized
ising but not always better
Neurobl
• Arises fsympat
• Adrena• Adrena• 7.2% (S• 10.2 pe• Most co• Male =
lastoma
from embryonal neuroblasts of thetic peripheral nervous systemal/abdomen most common siteal/abdomen most common siteSEER); ~650 cases per yearer million children <15yrsommon malignancy < 1yrFemale
Neurobllastoma
Metasta
Disease localization Initialbone marrow 87.3bone 66.1lymph nodes 18.6lymph nodes 18.6Liver 17.4Skin 2.8Intracranial/cerebral 9.1Intracranial/cerebral 9.1lung/pleura 4.7paratesticular 1.0Ovary 0.3Ovary 0.3Isolated local recurrenceIsolated metastatic recurrenceCombined local and metastaticCombined local and metastatic
atic sitesStage 4
1st recurrence35.246.68.98.97.5019.019.03.100017.058.124.924.9
MIBG (I-131-meta-iodobenzylguanidine) scan
Staging
Stage 1 Localized tumor confined toGTR +/- microscopic residuGTR +/ microscopic residu
Regional LN negatAdherent removed
Stage 2A Unilateral with incomplete gg p gLN negative (ipsila
Stage 2B Unilateral with complete oripsilateral LN posi
Stage 3 Tumor infiltrating across miunilateral tumor wimidline tumor with
St 4 Di i ti f t t dStage 4 Dissemination of tumor to dother organs excep
Stage 4S Localized primary tumor aswith disseminationwith dissemination(< 10 % of nucleat
g (INSS)
o the area of origin. ual disease;ual disease; tive (ipsilateral and contralateral)
d LN can be positive gross resectiongateral and contralateral) r incomplete gross resectionitive but contralateral LN negative idline +/- LN or ith contralateral LN involvement or h bilateral LN involvementdi t t l h d b lidistant lymph nodes, bone marrow, liver, orpt as defined in stage 4S.s defined for stage 1 or 2 n limited to liver skin and bone marrown limited to liver, skin and bone marrow ted marrow cells are tumor cells).
Stag
1 5 Gy x 3 if life threat1.5 Gy x 3 if life-threat
e 4S
tening liver distentiontening liver distention
PrognProgn
• Stage (4 versus LRStage (4 versus LR• MYCN amplificatio• Age (infants 12-18Age (infants, 12 18
adolescents, adults• LN only versus bony• LDH• Histology (Shimada)• Ferritin• Ferritin• 1p36 deletion• VMA/HVA• Symptomatic
nosisnosis
R/4s)R/4s)on8 months >18 months8 months, >18 months, s)ne +/- marrow
Clinical Stages of
4s
1 2 3 S rge1,2,3 Surge
44
f Neuroblastoma
ercure
ery
Hi h i k NB tHigh risk NB: st
Bulk disease M
Dose intensity LR
Surgical debulkingRTDD
t 4 1 Atage 4, >1 y Age
Minimal Residual Disease
Local radiationRadioimmunotherapyRadioimmunotherapyTargeted immunotherapyDifferentiation therapyDifferentiation therapy
Radiation for
21 G t i t• 21 Gy to primary tumo– 90% local control– 36 Gy boost to gross r
• Recommended in curre
• RT to residual MIBG +• CSI + boost with RIT f• Extremely effective pa
r high risk NB
b d ft GTRor bed after GTR
esidual – not effective?ent COG trial
+ or initially bulky metsfor CNS relapsepalliation of bone disease
W ld t l IJROBP 46 969 2000Wolden et al, IJROBP 46:969, 2000Croog et al, IJROBP 78:849, 2010
Stage 4 NB >1yStage 4 NB 1y1.2
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iagnosis
Children’s Oncology Group study 3891
Autologous SCTCis-retinoic acid
Matthay et al; NEJM. 341: 1165, 1999
Pediatric HodgkPediatric Hodgk
W
kin lymphomakin lymphoma
We have come a long way in the last century.
Where do we go from here?here?
Photo from Reed et al, 1902
Why do we useWhy do we use doses in c
lower radiationlower radiation children?
Late eLate e
• Growth deficits– Clinically nonsignificant with
• Willman et al. IJROBP 28:85
Th id b liti• Thyroid abnormalities– RR hypothyroidism = 17, hy
• Sklar et al J Clin Endocrino• Sklar et al. J Clin Endocrino
• Second cancers• Cardiovascular and Pulmo• Cardiovascular and Pulmo
– Outranks 2nd cancers for ea• Hancock et al. Semin Radiat
effectseffects
h low dose RT5, 1994
yperthyroidism = 8, nodules = 27ol Metab 85:4441 2000ol Metab 85:4441, 2000
onary Toxicityonary Toxicityrly mortalityt Oncol 6:225, 1996
Total Lymphoid Irstandard for most t
rradiation: 44 Gyteens until 1990’s
CCSSAn NCI-funded
Risk of ConResource Multiv
6
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ativ
e R
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Sex Age at Diagnosis
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gestive Heart Failure variate Analysis
≥250*≥35*250*
1 5
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1-5 6-150
Cardiac RT dose (Gy)
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cation, smoking, treatment era
Mulrooney BMJ 2009
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elat
ive
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0Sex
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Valvular Disease variate Analysis
>35*15-35*
>250*0
1-5
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<250
Cardiac RT dose
(Gy)
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n, smoking, treatment era
(Gy)
Mulrooney BMJ 2009
SecondStanford data 1Stanford data 1
20All Cancers (17.6
15Solid Tumors (13.2
Leukemia (3.3%
Lymphoma (1 6%ILIT
Y
10Lymphoma (1.6%
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R
00 42 86
TIME
d cancers1968 84 (n=1510)1968-84 (n=1510)%)
2%)
%)
%)%)
10 14 16 1812
E (Years)Tucker et al. NEJM 318:76, 1988
Breast cancer risk byBreast cancer risk by80
60
70
40
50
30
20
10
01050 15 201050 15 20
y attained age after HDy attained age after HD
25 30 35 40 4525 30 35 40 45
Bhatia et al, NEJM 334:12, 1996
Excess cancers f ll dfollowed
20
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sk
10 8.8 8.9
cent
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5Perc
0Males Females Breast
per 100 patients 2020 years
2.2 1 5
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2.20.8 1.5
Wolden et al. JCO 16:536, 1998
Relative risk of breRelative risk of bre30
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k
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ativ
e
0
5
0 20 21 240-20 21-24
Age at radiotherap
east cancer by ageeast cancer by age
25 29 30+25-29 30+
py (years)
Hancock et al, JNCI 85:1, 1993Wolden et al. JCO16:536, 1998
Do the data supDo the data suplower radiation do
pport efficacy ofpport efficacy of oses in children?
.Stanford, St Jud•Stage I-II favorable•VAMP x 4•VAMP x 4
•Response based IFRTResponse based IFRT•Assessed after cycle 2•CR: 15 Gy (7%)•PR: 25.5 Gy (92%)
•Results•5 year EFS 93%5 year OS 99%•5 year OS 99%
.de, Dana-Farber
Donaldson et al. JCO 20:3081, 2002
Do lower doses reDo lower doses re
• 110 patients received110 patients received – 18 developed SMN: cu
N
Leukemia 4
Thyroid 5
Breast 6Breast 6
Sarcoma 4
duce risk of SMN?duce risk of SMN?
15-25 Gy 1970-9015 25 Gy 1970 90umulative incidence 17%
SIR AER
91 19
53 23
72 8472 84
89 19
O'Brien et al. JCO 28:1232, 2010
SMN after Low Do
Anyy
Solid5 year y
Leu5 year
ose RT (15-25 Gy)
y SMNy
d tumorOS = 85%%
ukemiar OS = 0%
O'Brien et al. JCO 28:1232, 2010
Is radiotherapy npatiepatie
necessary in all nts?nts?
German GPOGerman GPO
• 1018 Patients• OPPA (OEPA) /COPP• 20-35 Gy IFRT for <CR
• Lowest risk groupDFS 94% / OS 99%– DFS 94% / OS 99%
– CR no RT = PR + RT • Int / high risk groupsInt / high risk groups
• No difference in survival• DFS 69% no RT vs 91% wi
Ru
OH-HD 95 trialOH HD 95 trial
th RT (p = 0.0001)(p )
uhl. IJROBP 51:1209, 2001 + ASTRO, 2008
CCG 5942
829 patients
501 with CR
1995-98
Nachman et al. JCO 20:3765, 2002
CCG 5942 LonCCG 5942 Lon
EFS 91% vs 83% p=0 004
0 90
1.00
EFS 91% vs 83%, p=0.004
0.50
0.60
0.70
0.80
0.90
estim
ate
0.10
0.20
0.30
0.40
EFS
e
ifrtnort
0.00
265 236(26) 220(8) 207(2) 192(5) 171(0) 151(1) 94(1) 18(0) 0(0)nort233 220(7) 211(5) 202(3) 187(0) 171(1) 152(3) 104(0) 24(0) 0(0)ifrt
at risk (event)
0 1 2 3 4 5 6 8 10 12
Years from randomization
ng-term resultsng-term results
OS 97% vs 96% p=0 5
0 90
1.00
OS 97% vs 96%, p=0.5
0.50
0.60
0.70
0.80
0.90
estim
ate
0.10
0.20
0.30
0.40OS
e
ifrtnort
0.00
265 260(2) 251(0) 238(0) 223(3) 199(2) 174(1) 106(1) 22(0) 0(0)nort233 226(1) 221(1) 212(2) 197(0) 181(1) 162(1) 109(0) 26(0) 0(0)ifrt
at risk (event)
0 1 2 3 4 5 6 8 10 12
Years from randomization
Wolden et al. JCO (in press), 2012
COG AHOD043COG AHOD043
AV PC* 3 kCR
PET 2 AV-PC*1 AV-PC*
AV-PC* q3 weeks
Eli ibilit
P
Eligibility:• Age <21 years • CS IA-IIA• No bulk disease or LPHL
1: Low Risk HL1: Low Risk HL
No RTR IV-DECA/RTrelapse
relapse21 Gy
RSCT
relapse
Keller, ASH abstract 2010
AHODE l St FEarly Stage Fa
• 275 subjects evaluable be• 275 subjects evaluable be• CR rate after 3 cycles of AVPC
• Medium follow
Entire Cohort (
2 year EFS 84%2 year OS 100%
0431bl HLavorable HL
etween 2/2006 and 12/2008etween 2/2006 and 12/2008C = 63.6% (lower than expected)w-up 25 months
CR (no IFRT)
PR (+ IFRT)
p Value
80%** 88% 0.11- -
**Study closed by DSMCStudy closed by DSMC
AHOD2 year2 year
• 227 subjects had evaluabj(3 weeks) of chem
CR (no IFRT) p VaPET1+ 65%**
0.0PET1- 87%
** CR paPET1 ca
yearyear
0431EFSEFS
ble PET results after 1 cycle ymotherapy (PET1)
alue PR (+ IFRT) p Value82%
005 0.04796%
atients with positive or equivocal alled back for IFRT if within one of completing chemotherapyof completing chemotherapy
Sh ld lShould early resther
d t isponse determine apy?py
AHOD0031: InterAHOD0031: Inter
• Test the paradigm of resp• Test the paradigm of resp– to decrease therapy for rap– to augment therapy for slowto augment therapy for slow
• All histologies, ages 0-21 • All Stages exceptAll Stages except
– Stage IA, IIA – no bulk
Stage IIIB IVB– Stage IIIB, IVB
• Accrued 1712 eligible pati
mediate Risk HLmediate Risk HL
onse based therapyonse-based therapy id early responders
w early respondersw early respondersyears
ents: 2002 –2009
Friedman, ASH abstract 2010
CSchema
RERABVE-PCX2
C
ABVE-PCX2< CR
RAN
SER
NDOMIIZE
CRIFRT: 21 Gy(standard arm)
RANCR ( )DOMI
No IFRT(reduced therapy arm)
ZE
IFRT: 21 Gy
ABVE-PCX2 + DECA X2 + IFRT: 21 GyDECA X2 + IFRT: 21 Gy
(augmented therapy arm)
ABVE-PCX2 + IFRT: 21 Gy(standard arm)
ResponsepReal – Time Centr
• Rapid early response• Rapid early response– >60% reduction in the pro
diameters of each lesiondiameters of each lesion
• Complete response• Complete response – >80% reduction in the pro
diameters of each lesiondiameters of each lesion
– Negative functional imagiNegative functional imagi– No extra-mediastinal resid
e criteriaral review by QARC
oduct of the perpendicular by CT scanby CT scan
oduct of the perpendicular by CT scanby CT scanPLUS
ng studyng studydual lymph aggregate > 2cm
Study participaSexMaleFemaleFemale
Age in yearsMeanMedian (range)
StageIA bulkIA bulkIIA bulkIAE, IIAEIBIBIIBIIIAIVA
81% (716) RER and 19% (3
ants (N = 1712)
908 (53%) 804 (47%)( )
14.615 2 (1 9 21 9)15.2 (1.9, 21.9)
82 (4 8%)82 (4.8%)614 (35.9%)
28 (1.6%)16 (0.9%)( )
363 (21.2%)353 (20.6%)256 (15.0%)
05) SER randomized
RER vs
0.90
1.00 RER
0.60
0.70
0.80
0.90
e su
rviv
al
SER
0.30
0.40
0.50
Even
t-fre
e
0.00
0.10
0.20
0 1 2
305 242 169 12:ser1369 1112 811 51:rer
risk (n)
0 1 2
P = 0.0001
s. SER
3 YR EFS = 87.3%
3 YR EFS = 77.9%
3 4 5 6 7
RERSER
124 75 32 5 0583 353 169 72 2
3 4 5 6 7Time (years)
IFRT vs. n
1.00 IFRT
0.70
0.80
0.90
urvi
val
No IFRT
0.40
0.50
0.60
vent
-free
su
0.10
0.20
0.30E
0.00
357 270 194 1233:IRFTrisk (n)
0 1 2 3
Tim
359 261 187 1134:NONE
P = 0.07**
no IFRT**
3 YR EFS = 87.9%
3 YR EFS = 85.4%
IFRTNo IFRT
72 25 3 0
4 5 6 7
me (years)
59 20 3 0
DECA vs
0 90
1.00
DECA
0 60
0.70
0.80
0.90
urvi
val
DECA
No DECA
0 30
0.40
0.50
0.60
vent
-free
su No DECA
0 00
0.10
0.20
0.30Ev
0.00
O153 116 82 605:DECA
risk (n)
0 1 2 3
Tim
151 110 82 596:NONE
P = 0.16
. no DECA
3 YR EFS = 80 2% 3 YR EFS = 80.2%
3 YR EFS = 75 6% 3 YR EFS = 75.6%
DECANo DECA
35 17 4 0
4 5 6 7
me (years)
35 14 1 0
Role oRole o
• PET superior to galliumPET superior to gallium– For staging– Response evaluationp– RT field design– Can PET response
d t i d f RT?determine need for RT?• Further study needed
St d di d l– Standardized values– Bone lesions– Utility for follow-up– Utility for follow-up
EHines-Thoma
of PETof PET
Esiashvili et al. ASTRO, 2008s et al. Pediatr Blood Cancer 51:198, 2008
Is involved node t1970 19
Total Lymphoid Irradiation (TLI)
Involved-Fie(IF
therapy adequate?995 2008
eld RadiationFRT)
Involved Node Radiation (INRT)
Current study: highCOG AHCOG AH
ABVE
ABVEPE
ABVE
ABVE
CPE
RER
ABVE-PC*
ABVE-PC* *Only if P
Risk AdaptedRT: 21 Gyy
h risk HD (IIIB, IVB)OD0831OD0831
E PC*
E-PC*ET-1
E-PC*
E-PC
CTET-2*
Ifos/VinoSER
ABVE PC*
Ifos/Vino
Ifos/Vino
ET-1 positive
ABVE-PC*
ABVE-PC
Modified IFRT: 21 Gy
IFRT in highg
Sites of RT for RER patients:Sites of RT for RER patients:• Initial bulky disease: MMR > 1
macroscopic splenic nodules) • Non-bulky areas that are PET2 n
Sites of RT for SER patients:• Initial bulky disease• Slow responding non bulky dis• Slow responding non-bulky dis• Residual disease > 2.5 cm at e
h risk studyy
/3, nodal masses >6 cm and
negative will not be targeted for RT
sease (PET2+)sease (PET2+)nd of chemotherapy
WilmsWilms
• Approximately 450-500 cases
• 5th most common pediatric m
• Median age: 3.5 years fo2.5 years fo
• Common signs/symptoms:– Abdominal mass/distensio– Abdominal pain (37%)– Fever/Malaise (23%)– Hematuria (21% usually mHematuria (21% usually m– Hypertension (25%)
TumorTumor
s annually in U.S.
alignancy
or unilateral tumoror bilateral tumors (6%)
on (83%)
microscopic)microscopic)
Wilms Tumor
• Abnormal proliferation of metap• 1–2% with family history, majo• Associated with congenital an
Wilms tumor gene WT1 (located at 11pkidney development. 20% of all Wilms•WAGR syndrome (WT1)
•Wilms tumor, aniridia, genitourinar•Denys-Drash syndrome (WT1)
–Wilms tumor, pseudohermaphrod
Wilms tumor gene WT2 (11p15) proto-•Beckwith-Wiedemann syndrome (WT
Macroglossia hemihypertrophy g–Macroglossia, hemihypertrophy, g
Pathogenesisg
anephric blastemapority are sporadic omalies in 10–13% of cases
p13) tumor suppressor gene specific for s tumors carry WT1 mutations.
ry malformations, and mental retardation
itism, and glomerulopathy
-oncogene associated with IGF22)gigantism and umbilical herniagigantism, and umbilical hernia
WilmsWilms TumorTumor
2007 AREN StStage CriteriaStage Criteria
I Tumor limited to kidney, completely reTumor not ruptured or biopsied prior top p psinus not involved or <2 mm. Negative
II Extends beyond kidney but completely (e.g. penetration of renal capsule or blovessels outside renal parenchyma conta
III S: Spillage, including localL: Lymph nodes involvedU: UnresectableR: RuptureP: Peritoneal implants or positive marg
IV Distant metastases
V Bilateral
Favorable Histology (not anaplastic, cleaAnaplastic 10 year OS: St
taging Systema 10 yr OSa 10 yr OS
(FH*)sected. Renal capsule intact.
o resection. Vessels of renal 97%
e marginsexcised. Regional extension
ood vessels >2mm); blood 93%
ain tumor. Negative margins.90%
gins80%
78%
ar cell, rhabdoid) accounts for 90% of cases tage I-III:49%, Stage IV: 18%
Treatment RecStage
I –II FHI Anaplasia
Nephrectomy → viN RTI Anaplasia No RT
III-IV FHII-IV Focal Anaplasia
Nephrectomy → Rvincristine/dactinom
II-IV Diffuse AnaplasiaI-IV Clear Cell Sarcoma
Nephrectomy → Rvincristine/adriamy
I-IV Rhabdoid tumor Nephrectomy → Rcarboplatin/etoposi
Bilateral Wilms Biopsy and stage eBilateral Wilms Biopsy and stage eevaluate response aafter resection → sclear cell, rhabdoid
commendationsTreatment
incristine/dactinomycin pulse intensive (18 wks)
RT → chemotherapy mycin/adriamycin (24 wks)
RT → chemotherapy ycin/etoposide/cyclophosphamide (24 wks)
RT → chemotherapy ide/cyclophosphamide (24 wks)
each kidney → give chemo for highest stage theneach kidney → give chemo for highest stage then at 5 wks. If possible to leave >2/3 each kidney surgery. RT for Stage III/IV FH, III/IV anaplasia, d.
Wilm
• Start RT by day 9 post-op; AP/P10 8 G t kid t• 10.8 Gy to pre-op kidney + tumo
• Peritoneal seeding/rupture: wh• Lung Metastases: whole lung R• Lung Metastases: whole lung R
• Current investigational protocolsg p– Stratifying risk based on LOH in ch– Elimination of WLRT for patients w
Highest risk: 19 8 Gy for rhabdoid– Highest risk: 19.8 Gy for rhabdoid – IMRT for whole lung radiation
ms RT
PA fields1 i PA dor + 1cm margin + PA nodes
ole abdomen/pelvis RT to 10.5 GyRT: 12 GyRT: 12 Gy
s:hromosome 1p and 16q (poor prognosis)with CR by week 6 (no 1p / 16q loss)tumors and stage III diffuse anaplasiatumors and stage III diffuse anaplasia
Retinoblastoma (RRetinoblastoma (R
• 200 patients annu200 patients annu
• Median age = 2 y– Hereditary cases ea
• Male = Female
• Unilateral 75%– 15% multifocal
• Bilateral 25%– 100% multifocal (2-2
RB): EpidemiologyRB): Epidemiology
ually in U.Sually in U.S
yearsrlier than sporadic
20 tumors)
Epidem
U iHereditary UniBila
Sporadic
0% 20% 40% 60
miology
il t lilateralateral
% 80%
GeneGene
• Autosomal dominant in– nearly complete penetry p p
• Autosomal recessive g– located on chromosom
– tumor suppressor genepp g
eticsetics
nheritance patternrance: 45%
gene: RB1me 13
e
Two-hit hy
1st hitRB1 wt
RB1 wt
1st hit
RB1 mut
RB1 wt
ypothesis
2nd hitproliferationproliferation
RB1 mut
RB1 mut
RB1 mut
RB1 mut
RB1RB1
RB1 mut
RB1 mut
RB1 mut
RB1 mut
RB1 mut
RB1 mut
StainedStained sectionsection
RB: ClinicalRB: Clinical
• Most are intraocular in U• Most are intraocular in U– Late diagnosis is commo
• Leukocoria: “cat’s eye re– Large visible tumor or retg
• Strabismus: esotropia oM l i l t ith– Macular involvement with
• Screening of children wi
presentationpresentation
U SU.Son in developing countries
eflex”tinal detachment
r exotropiah l f t l i ih loss of central vision
th family history
LeukoLeukoocoriaocoria
Patterns oPatterns o
• Arises in the retina and• Arises in the retina and – Endophytic or exophytic
M “ d” th it– May “seed” the vitreous – Spreads along optic nerv– May extend outside the g– Extra-orbital spread in th
• “Trilateral” RB: involvem– Rare (6%) hereditary forRare (6%) hereditary for
of Spreadof Spread
proliferates rapidlyproliferates rapidlygrowth
d fill th l band fill the globeve toward brainglobe, into the orbit
he CNS or bone marrow
ment of the pineal glandrm with poor prognosisrm with poor prognosis
VitreousVitreous seedingseeding
WorkWork
• Diagnosis made by op• Diagnosis made by op– Pathologic confirmation no
F d di d/ h– Fundus diagram and/or ph
• Ancillary tests– Ultrasound helpful when fu– CT and MRI scan less use
• Not reliable for spread a• Calcifications may or m
artifact
k-upk-up
phthalmologic examphthalmologic examot requiredh khotos taken
undus not seen wellefulalong nerveay not be present & can cause
Indirect ophthaIndirect ophthaalmoscopy viewalmoscopy view
Reese-Ellsworth staReese-Ellsworth sta
– Group I
• < 4 disk diameters, at or behind
– Group II
• 4-10 disk diameters, at or behi
– Group III
• Anterior to equator or solitary t
– Group IV
• Multiple tumors >10 disk diame• Multiple tumors >10 disk diame
– Group V
• Tumors involving more than hag
aging classificationaging classification
d equator
nd equator
umor >10 disk diameters behind equator
eters or extending anterior to ora serrataeters or extending anterior to ora serrata
alf of the retina or vitreous seedingg
Treatment coTreatment co
G lGoals
1. Curing patient og p
2. Preserving visio
3. Minimizing risk
4 Cosmesis4. Cosmesis
onsiderationsonsiderations
of retinoblastoma
on
of 2nd cancer
TreatmenTreatmen
• Enucleation: removal o• Enucleation: removal o• Cryotherapy or laser p• Chemotherapy: system• External beam indicatio
– Preservation vision; tum– Tumor too extensive fo– Salvage after failure of – Extraocular or metastatExtraocular or metastat
t Optionst Options
of the eyeof the eyehotocoagulation
mic or intra-arterialons:
mor in macular focal therapypyfocal therapytic diseasetic disease
Episcleral plaquEpiscleral plaqu• Iodine-125: apical dos
– Cobalt and other sourc– Sutured to sclera by oSutured to sclera by o
• Complications rare– Cataracts for anterior t– Second malignancy/ o
e brachytherapye brachytherapyse 40-42.5 Gyces used historicallyphthalmologistphthalmologist
tumorsoptic neuropathy risk negligible
Buys et al. Arch Ophthal 101:1206, 1983
External beExternal be
• Opposed lateral D-shapepp p• Cover entire retina, vitreou
• Isocenter at fleshy canthusIsocenter at fleshy canthus
• “Beam-split” to reduce risk
• Protons• Protons
• Superior/inferior oblique • Local control 84% (Group
• IMRT or protons
eam: 45 Gyeam: 45 Gy
e fields for bilateral RBus & 1cm of optic nerve
s (posterior lens)s (posterior lens)
k of cataract
for unilateral RBI-III) at MSKCC, n=182 eyes*
Blach et al. IJROBP 35:45, 1996
External beaExternal bea
• Five year survival isFive year survival is
• Preservation of eye w– 95% for stage I-III
– 50% for stage IV-V– 50% for stage IV-V
• Acuity is excellent (2– Poor if macula involv
**Egb
m RT resultsm RT results
>90% in the U S>90% in the U.S.
with EBRT*
20/40) in most patients**ved
bert et al. Arch Ophth 96:1826, 1978
*Blach et al. IJROBP 35:45, 1995
ComplicComplic
• Cataract formation– Threshold is 10-20 Gy fr– Long term incidence 22%
• Dry eye– Uncommon if conjunctiv
• Retinopathy– Low risk with doses < 45
• Bone growth abnorm– Occur with EBRT or enu
cationscations
ractionated% at MSKCC
a and lacrimal glands spared
5 Gy
malitiesucleation
SecondSecond
• Increased risk with germIncreased risk with germ– Increased risk regardles
– Higher risk in RT field
– Higher mortality for in-fieg y
– Sarcomas most commo
Hi h li f 2– Higher mortality from 2n
CancersCancers
mline RB mutationmline RB mutationss of RT
eld sarcomas
on (bone and soft tissue)d h RB i U Snd tumors than RB in U.S.
RT & Seconnd cancers
SecondSecond
• Hereditary RBHereditary RB– Cumulative incidence 5
– Higher risk for patients
– 10-year incidence of 3rd
• Nonhereditary RB– Cumulative incidence 5
WWAbra
Ab
CancersCancers
51% at 50 years
<1 vs >1year (p=.004)d cancer is 22%
5% at 50 years
Wong et al JAMA 278:1284-5 1997Wong et al. JAMA 278:1284-5, 1997amson et al. Ophthal 105:573-580, 1998bramson et al. Ophthal 108:1868, 2001
Suzanne Wolden MD FACRSuzanne Wolden, MD FACRDept. Radiation OncologyMemorial Sloan-Ketteringg
1275 York AvenueNew York, NY 10028