State of the Art Radiotherapy for Pediatric Tumors

SuzanneSuzanne L.L. Wolden,Wolden, MDMD MemorialMemorial SloanSloan--KetteringKettering CancerCancer CenterCenter 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 Æ 2D linac Æ 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 lymphoma from Reed’s 1902 paper 1970 1995 2009

Total Lymphoid Irradiation Involved-Field Radiation Involved Node Radiation (TLI) (IFRT) (INRT) 44 Gy 21 Gy 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

1.2

N7=CAV/PV + 131I-3F8 + 3F8 1.0 N6=CAV/PV + 3F8 N5=CAV/PV + ABMT

.8 N4=CAV + ABMT

.6 N7 (94-99) N6 (89-94) .4

Proportion alive progression-free N5 (87-89)

.2

N4 (80’s) 0.0 0 50 100 150 200 250

Months from diagnosis

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

1.0 Orbit 0.9 GU non-B/P 0.8 H & N 0.7 GU B/P 0.6 PM Extremity Other 0.5 0.4 0.3 0.2

Failure-free Survival Failure-free 0.1 Log Rank Test: p<0.001 0.0 0 1 2 3 4 5 6 Years 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, 2001 Donaldson 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

1.0 0.9 0.8 Conventional 0.7 0.6 Hyperfractionated 0.5 0.4

Failure-free Survival 0.3 0.2 0.1 Log Rank Test: p=0.76 0.0 0 1 2 3 4 5

Years 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

100 orbit/head &neck 90 parameningeal 80 70 60 50 40 30 p = 0.60

% Local Control 20 10 0 0123456 Years Fusion of CT, MRI, and PET Scans Infratemporal fossa with PM extension Parameningeal RMS: Dose Comparison (IMRT v Protons) (Kozak, Yock, in press IJROBP) Results: • Improved dose conformality of protons spared most normal tissues examined except for a few ipsilateral structures such as the parotid and cochlea. % Dose 105 100 80 60 40 20 Bone sparing for soft tissue sarcoma Ewing sarcoma: Askin tumor + whole lung IMRT for Osteosarcoma of C2

100% 90% 70% 50%

PTV Cord Whole Abdomen / Pelvis IMRT for DSRCT Whole Abdomen / Pelvis IMRT for 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

IMRT 2D 3D Craniospinal RT with protons Intrathecal radioimmunotherapy

131I • 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

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

Linear X-ray sources accelerator Synchrony™ camera SynchronyManipulator™ camera Robotic Delivery System

Image detectors TreatmentTreatment couch couch 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, MD Dept of Radiation Oncology Memorial Sloan-Kettering 1275 York Avenue New York, NY 10021

Phone: 212-639-5148 E-mail: [email protected]