State of the Art Radiotherapy for Pediatric Tumors Suzanne L. - PowerPoint PPT Presentation

State of the Art Radiotherapy for Pediatric Tumors Suzanne L. Wolden, MD Suzanne L. Wolden, MD Memorial Sloan- -Kettering Cancer Center Kettering Cancer Center Memorial Sloan

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 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 1 st 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 + 131 I-3F8 + 3F8 1.0 N6=CAV/PV + 3F8 Proportion alive progression-free N5=CAV/PV + ABMT N4=CAV + ABMT .8 .6 N7 (94-99) N6 (89-94) .4 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 H & N Failure-free Survival 0.8 GU B/P 0.7 PM 0.6 Extremity Other 0.5 0.4 0.3 0.2 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 Failure-free Survival 0.9 0.8 Conventional 0.7 0.6 Hyperfractionated 0.5 0.4 0.3 0.2 Log Rank Test: p=0.76 0.1 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 orbit/head &neck 100 90 parameningeal 80 % Local Control 70 60 50 40 30 p = 0.60 20 10 0 0 1 2 3 4 5 6 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

Askin tumor + whole lung Ewing sarcoma:

IMRT for Osteosarcoma of C2 100% Cord 90% 70% 50% PTV

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

IMRT Medulloblastoma boost 3D 2D

IMRT 3D 2D Medulloblastoma: cochlea dose

Craniospinal RT with protons

Intrathecal radioimmunotherapy 131 I • Anti-GD2 IgG2 Ab (3F8) conjugated to 131 I • 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 Manipulator Synchrony ™ Robotic Delivery System camera Image detectors Treatment couch Treatment 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: woldens@mskcc.org