State of the Art Radiotherapy for Pediatric Tumors Suzanne L. Wolden, MD Memorial Sloan-Kettering 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 lymphoma from 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 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): 1.2 treatment outcome Proportion alive progression-free 1.0.8.6.4.2 N7 (94-99) N7=CAV/PV + 131 I-3F8 + 3F8 N6=CAV/PV + 3F8 N5=CAV/PV + ABMT N4=CAV + ABMT N6 (89-94) N5 (87-89) 0.0 0 N4 (80 s) 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 Failure-free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Log Rank Test: p<0.001 Extremity Orbit GU non-b/p Other 0 1 2 3 4 5 6 Years H & N GU B/P PM
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 Failure-free survival for patients with Group III tumors by radiation schedule 1.0 0.9 0.8 0.7 Conventional 0.6 Hyperfractionated 0.5 0.4 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 % Local Control 100 90 80 70 60 50 40 30 20 10 0 orbit/head &neck parameningeal p = 0.60 0 1 2 3 4 5 6 Years
Fusion of CT, MRI, and PET Scans
Infratemporal fossa with PM extension
Results: Parameningeal RMS: Dose Comparison (IMRT v Protons) (Kozak, Yock, in press IJROBP) 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 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 8 131 I 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 X-ray sources Synchrony camera Synchrony Manipulator camera Linear accelerator Robotic Delivery System Treatment Treatment couch couch Image detectors
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