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

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44

f Neuroblastoma

ercure

ery

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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

on-fr

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250200150

Cheung et al Med Ped Onc 36: 227, 2001

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

Ris

k* 4

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ativ

e R

2

3

F

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R

0

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Sex Age at Diagnosis

P <0.05 * Adjusted for race, BMI, income, educ*

gestive Heart Failure variate Analysis

≥250*≥35*250*

1 5

15-35* <250*0

1-5 6-150

Cardiac RT dose (Gy)

Anthracycline(mg/m2)

cation, smoking, treatment era

Mulrooney BMJ 2009

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6

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sk*

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elat

ive

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2

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4

F

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0

1

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Age at Diagnosis

(yrs)

0Sex

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Valvular Disease variate Analysis

>35*15-35*

>250*0

1-5

6-150

<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%

RO

BA

BI

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% P

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

1515.6

sk

10 8.8 8.9

cent

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5Perc

0Males Females Breast

per 100 patients 2020 years

2.2 1 5

Sarcoma NHL Leukemia

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Wolden et al. JCO 16:536, 1998

Relative risk of breRelative risk of bre30

20

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k

10

15

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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

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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

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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

212-639-5148woldens@mskcc.org