State of the Art Radiotherapy for Pediatric Tumors

Suzanne L. Wolden, MDSuzanne L. Wolden, MDMemorial SloanMemorial Sloan--Kettering Cancer CenterKettering Cancer Center

Introduction

• Progress and success in pediatric oncology• Examples of low-tech and high-tech radiation

solutions in common pediatric cancers– Hodgkin lymphoma– Neuroblastoma– Rhabdomyosarcoma– Medulloblastoma

• Global perspective

Distribution of pediatric malignancies

Pediatric cancer cure rates

Evolution of radiation techniques• External beam radiation therapy

– Co-60 2D linac 3D treatment– Stereotactic radiosurgery– Intensity modulated radiation therapy (IMRT)– Protons, electrons, other particles– Image guided radiation therapy (IGRT)

• Brachytherapy– Permanent seeds– Remote afterloading: LDR -> HDR– Intraoperative radiation therapy (IORT)

7 year old boy with Hodgkin lymphomafrom Reed’s 1902 paper

1970 1995 2009

Total Lymphoid Irradiation (TLI)

44 Gy

Involved-Field Radiation(IFRT)21 Gy

Involved Node Radiation (INRT)21 Gy

CCG 5942 Hodgkin lymphoma trial

• Chemotherapy by stage of disease• Randomization +/- 21 Gy IFRT• Study closed at 1st interim analysis

– 3 year EFS 93% vs 85% favoring RT (p<.01)– all subgroups benefitted from radiation

Nachman et al. JCO 20:3765, 2002

Hodgkin lymphoma techniques

• Advances in imaging (PET) have significantly impacted RT field design

• IMRT and protons have no obvious benefit over AP/PA fields for most cases

Neuroblastoma

• 650 cases per year in U.S.• Majority of patients are < 5 years of age• Radiation is used for primary site, lymph nodes,

and bone metastases in high risk patients• Local control 90% at primary site with RT• Most effective palliative therapy for metastases

Kushner et al., JCO (2001) 19:2821-28

Stage 4 neuroblastoma (>1 year age): treatment outcome

Months from diagnosis

250200150100500

Pro

porti

on a

live

prog

ress

ion-

free

1.2

1.0

.8

.6

.4

.2

0.0

N7=CAV/PV + 131I-3F8 + 3F8N6=CAV/PV + 3F8

N5=CAV/PV + ABMTN4=CAV + ABMT

N4 (80’s)

N6 (89-94)

N5 (87-89)

N7 (94-99)

Cheung et al, Med Ped Onc 36:227, 2001

Neuroblastoma: primary site 21 Gy

Neuroblastoma bone metastases: Brain sparing whole skull RT

4 months

Pretreatment right adrenal primary tumor

Local recurrence after chemotherapy, surgery

and 21 Gy external beam

Intraoperative radiation therapy

Rhabdomyosarcoma

• The most radiosensitive sarcoma• Majority of patients (in the U.S.) receive RT

– Definitive local control for Group III– Post-operatively

• Group I (alveolar or undifferentiated histology)• Group II (positive margins)• Group III (after second look surgery)

Survival by treatment era

Log Rank Test: p<0.001

Extremity

GU B/P

GU non-B/P H & N

Orbit

Other PM

Failure-free survival for local/regional tumors by primary site

0.00.10.20.30.40.50.60.70.80.91.0

Years0 1 2 3 4 5 6

Failu

re-fr

ee S

urvi

val

IRS IV (1991-1997)

• 5-yr local control for Group III RMS– Extremity 96% – Orbit 95%– Bladder/prostate 90%– Head and neck 88%– Parameningeal 84%– Other 90%.

Crist et al. JCO 19:3091, 2001Donaldson et al. IJROBP 51:718, 2001

RT for PM RMS at age 4 in 1978

Failure-free survival for patients with Group III tumors by radiation schedule

Years

Log Rank Test: p=0.76

Hyperfractionated

0.00.10.20.30.40.50.60.70.80.91.0

0 1 2 3 4 5

Conventional

Failu

re-fr

ee S

urvi

val

FDG-PET scan for staging MSKCC experience

• 21 patients, 84 sites evaluated pre-treatment– correlated with standard imaging and pathology– all primary tumors PET positive– sensitivity 81%

• some missed nodal and bone metastases– specificity 97%– Therapy altered in 3 of 21 (14%) cases

• due to LN involvement detected only on PET

Klem et al. J Pediatr Hematol Oncol 29:9, 2007

• 2 year old with alveolar rhabdomyosarcoma of the left thigh.

• PET scan shows pelvic node involvement

IRS V (1999-2004)

• Experimental dose reductions for selected patients:– Group I alveolar/undifferentiated: 41.1 -> 36 Gy– Group II N0: 41.4 -> 36 Gy– Group III orbit/eyelid: 50.4 -> 45 Gy– Group III “second look surgery”– negative margins: 50.5 -> 36 Gy– microscopically + margins: 50.4 -> 41.4 Gy– Group III requiring 50.4: eligible for “conedown”

IMRT for H&N rhabdomyosarcoma

• 28 patients, median age 8 (1-29) years• Primary sites

– 21 parameningeal• 71% with intracranial extension (ICE)

– 4 other head and neck and 3 orbit• Tumor greater than 5 cm: 57%• Involved regional lymph nodes: 25%

Wolden et al. IJROBP 61: 1432, 2005

Local control with IMRT

0102030405060708090

100

0 1 2 3 4 5 6Years

% L

ocal

Con

trol

p = 0.60

parameningeal

orbit/head &neck

Fusion of CT, MRI, and PET Scans

Infratemporal fossa with PM extension

Results:• Improved dose conformality of protons spared most normal

tissues examined except for a few ipsilateral structures such as the parotid and cochlea.

Parameningeal RMS: Dose Comparison (IMRT v Protons)

(Kozak, Yock, in press IJROBP)

% Dose10510080604020

Bone sparing for soft tissue sarcoma

Ewing sarcoma: Askin tumor + whole lung

IMRT for Osteosarcoma of C2

100%90%70%50%

PTVCord

Whole Abdomen / Pelvis IMRTfor DSRCT

Whole Abdomen / Pelvis IMRTfor DSRCT

Lower Eyelid RMS

Custom Eye Shield

Electron set-up

Extremity brachytherapy

Interstitial Tongue Brachytherapy

Medulloblastoma

• Common brain tumor in the posterior fossa• Requires craniospinal radiation & chemotherapy• Survival is 60-85% depending upon stage• IMRT or protons can be used for the “boost” to

spare inner ears and other normal tissues

Medulloblastoma

• MRI w/ contrast of entire neural axis• Lumbar puncture

Medulloblastoma boost

2D 3D IMRT

Medulloblastoma: cochlea dose

IMRT2D3D

Craniospinal RT with protons

Intrathecal radioimmunotherapy

• Anti-GD2 IgG2 Ab (3F8)conjugated to 131I

• IT by Ommaya reservoir• 2 mCi test dose, followed

by 10 mCi 7 days later• CSF dosimetry: 15-80 cGy/mCi• 18 Gy CSI w/ IMRT tumor-bed

boost to 5400• Concurrent vincristine, then

vincristine, cisplatin, CCNU x 8

131I

Kramer K, et al. JCO, 2007

Image-guided radiotherapy (IGRT)

• Respiratory Gating

• Diagnostic level X-rays– KV plain films– Fluoroscopy

• Cone-beam CT

Radiosurgery: Cyberknife

Synchrony™

camera

Treatment couch

Synchrony™

camera

Treatment couch

Linearaccelerator

Manipulator

Imagedetectors

X-ray sources

Robotic Delivery System

Conclusions• Radiation therapy plays a vital role in treating

childhood cancer.• New radiation technologies promise improve

tumor control with fewer late effects.• Older techniques remain useful in many cases.• Access to treatment is limited for the majority

of the world’s children.• Cost-effectiveness of new therapies and global

resource allocation is a critical issue.

Suzanne L. Wolden, MDDept of Radiation OncologyMemorial Sloan-Kettering 1275 York AvenueNew York, NY 10021

Phone: 212-639-5148E-mail: woldens@mskcc.org