2.radiotherapy in infant brain tumors...7/1/2015 1 arnold c. paulino, m.d. professor of radiation...

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A R N O L D C . P A U L I N O , M . D .P R O F E S S O R O F R A D I A T I O N O N C O L O G Y

M D A N D E R S O N C A N C E R C E N T E RA N D T E X A S C H I L D R E N ’ S H O S P I T A L

Radiotherapy in Infant Brain Tumors

Radiotherapy in Infant Brain Tumors

1. Try to Avoid Irradiation2. If radiation needs to be given, try to use very

conformal radiotherapy fields

Goals and Objectives

To gain an understanding of problems associated with irradiation of the brain in the very youngTo gain an understanding of recent trends in management of infant brain tumorsTo gain familiarity with different radiotherapy technology available for treatment of pediatric brain tumors

Primary Brain and CNS Tumors (0-14 years)

2007-2011

Ostrom QT et al Neurooncol 2015 (in press)

Central Brain Tumor Registry of the United States

Brain Tumors (0 to 1 Year)


Brain Tumors (1 to 4 years)


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Brain Tumor Type and Age


Brain Tumor Survival Rates (0-1 Year)

Histology N 2 Years 5 Years 10 Years

Pilocytic Astrocytoma 74 91.8% 80.1% 80.1%

Other Low Grade Glioma 59 90.5% 77.1% 70.7%

High Grade Glioma 69 54.1% 54.1% 54.1%

Ependymoma 51 70.6% 60.1% 51.4%

Medulloblastoma 65 48.6% 41.6% 38.2%

ATRT 67 19.7% 0% 0%

All Brain Tumors 636 61.0% 55.3% 53.2%


Brain Tumor Survival Rates (1-4 Years)

Histology N 2 Years 5 Years 10 Years

Pilocytic Astrocytoma 685 98.5% 97.5% 95.9%

Other Low Grade Glioma 254 92.4% 88.9% 88.9%

High Grade Glioma 308 34.7% 27.3% 24.4%

Ependymoma 309 85.8% 71.4% 59.4%

Medulloblastoma 388 71.4% 62.3% 58.0%

ATRT 111 36.7% 33.5% 33.5%

PNET 205 62.5% 54.4% 49.4%

All Brain Tumors 2758 78.0% 71.9% 68.6%


Rapid postnatal growth which slows down in adolescenceExamples include brain, kidney, heart and lung

Neural Growth Pattern

Brain

Most sensitive during fetal period but postnatally during first few years of lifeMost neurons present at birth but brain is still in an “unfinished” stateIncrease in axonal growth, dendritic arborization and synaptogenesis

Brain

Myelin formation well developed at the second year of life and continues in some tracts until 20-30 yearsBy age 6, most children have attained adult brain size

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Neurogenesis

Barani IJ et al. Int J Radiat Oncol Biol Phys 2007; 68:324-33

Impact of Age in Low Grade Glioma

Merchant TE et al. J Clin Oncol 2009; 27:3691-7

Neurocognitive Effects

N Older Average Risk

OlderHigh Risk

YoungerAverage Risk

YoungerHigh Risk

Intercept SlopePoints/yr

Intercept SlopePoints/yr

Intercept SlopePoints/Yr

Intercept SlopePoints/Yr

IQ 104 97.08 -0.42 97.00 -1.56 93.73 -2.41 94.05 -3.71

Reading 91 97.24 -2.05 99.26 -1.05 100.25 -4.81 95.94 -3.90

Spelling 90 95.65 -2.62 94.30 1.02 90.68 -2.60 97.14 -5.31

Math 93 94.12 -1.84 92.91 0.37 87.80 -0.77 96.00 -3.73

Mulhern RK et al. J Clin Oncol 2005; 23:5511-9 Desai SS et al. Int J Radiat Oncol Biol Phys 65:1222-7, 2006

Moyamoya Syndrome

Orbital and Midfacial Growth Retardation

Retinoblastoma patients treated from 1972-1988 at Utrecht University

Imhof SM et al. Ophthalmology 1996; 103:263-8



Measurement(mm)

Irradiated OrbitsMean +/- SD

Nonirradiated OrbitsMean +/- SD

P-value

Width 23.8 +/- 2.0 27.5 +/- 1.9 < 0.001

Height 23.7 +/- 3.3 27.6 +/- 3.0 < 0.01

Edge-tragus 59.9 +/- 4.7 63.5 +/- 3.8 < 0.01

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Age Group(months)

No. of Orbits

Width (mm)Mean +/- SD

Height (mm)Mean +/- SD

Edge-Tragus (mm)Mean +/- SD

0 to 3 24 22 +/- 3.3 21.4 +/- 2.9 56.2 +/- 6.0

3 to 6 22 23.1 +/- 3.4 23.2 +/- 3.4 60.1 +/- 5.1

6 to 12 21 25.5 +/- 2.2 24.9 +/- 2.7 62.1 +/- 6.1

>12 10 26.3 +/- 2.7 25.4 +/- 2.4 65.1 +/- 4.1



Craniospinal Irradiation (Medulloblastoma)

Radiotherapy Volume

SURVIVAL ACCORDING TO RT VOLUME

Posterior Fossa only

Posterior fossa + spine

Craniospinal

University of Lund

5% 25% 53%

University of Toronto

0% 53%

Strong Memorial Hospital

No RT: 0%Whole brain RT: 20%

50%

Radiobiology

Tumor Mean Inactivation Dose (Gy)

SF2

Wilms’ tumor 1.26 21

Burkitt’s lymphoma 1.38 24

Medulloblastoma 1.53 27

Neuroblastoma 1.80 35

Osteosarcoma 2.12 42

Melanoma 2.51 51

Glioblastoma 3.10 58

Deschavanne PJ, Fertil B. Int J Radiat Oncol Biol Phys 1996; 34:251-66

Craniospinal Irradiation

LateEffects

Neurocognitive

Auditory

Endocrine

SecondTumor

Gastrointestinal

Pulmonary

Cardiovascular

Musculoskeletal

Dental

Psychosocial

Visual

I SWEAR by Apollo the physician and Aesculapius ……..I will follow that system of regimen which, according to my ability and judgment, I consider for the benefit of my patients, and abstain from whatever is deleterious and mischievous…..

excerpt from the Hippocratic Oath

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Delaying or omitting radiotherapy

Popular approach in the 80s and 90s particularly in children < 3 years with brain tumorsCraniospinal radiotherapy is delayed until patient is 3 years or older in medulloblastomaInvolved field radiotherapy delayed until patient in 3 years or older in ependymoma, malignant glioma

Baby POG Study

Duffner PK et al. N Engl J Med, 1993; 328:1725-31

Baby POG Study

Duffner PK et al. N Engl J Med, 1993; 328:1725-31

62 children received 2 rounds of 2 cycles of VCR, CPM followed by 1 cycle of VP-16 and CDDP after resectionChemotherapy given from 12-24 months until child turned 3 years1- and 2-year PFS rates were 42% and 34% (medulloblastoma) and 58% and 42% (ependymoma)

CCG-921

82 children < 18 months of age with CNS PNET or ependymoma had surgery followed by 8 cycles of “8 in 1” chemotherapyRadiotherapy was administered to only 9 children prior to progression (involved field after two cycles or CSI after 1 year)3-year PFS was 22% for medulloblastoma and 26% for ependymoma

Geyer JR et al. J Clin Oncol 1994; 12:1607-15

HIT-SKK ‘92 for Medulloblastoma

After surgery, 43 children < 3 years received 3 cycles of intravenous chemotherapy and intraventricular methotrexate. Treatment was terminated if a complete remission was achieved.

Rutkowski S et al. N Engl J Med 2005; 352:978-86

HIT-SKK ‘92 for Medulloblastoma

Rutkowski S et al. N Engl J Med 2005; 352:978-86

19/23 evaluable pts had asymptomaticleukoencephalopathy

5-year PFS: 82% in those with complete resection and M0 disease (17 patients)

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Medulloblastoma Molecular Subtypes

Wingless-type Murine Mammary Tumor Virus Integration Site (WNT)

Sonic Hedgehog (SHH)

Type C Type D

Prognosis Excellent Good Dismal Fair

Frequency 10% 25% 30% 35%

Typical Age Older childhood Infant and adult Childhood Childhood

Male: Female Ratio 1:1.7 1:0.5 1:0.7 1:0.5

Typical histology Classic Desmoplastic or classic Classic or anaplastic Classic or anaplastic

Metastatic disease 0% 7% 75% 31%

Cytogenetic markers Monosomy 6 9q loss Isochromosome 17q Isochromosome 17q

Molecular markers Beta-catenin SFRP1 or GAB1 MYC unknown

Clinical strategy Reduction in therapy SHH pathway inhibitors,Omit radiotherapy in young children

Intensified therapy, novel therapeutics

Research focus needed

Anatomically Distinct Types of Medulloblastoma

Gibson P et al. Nature 2010; 468:1095-9

HIT 2000 HIT-SKK 2000 for Medulloblastoma

von Bueren AO et al. Neuro-oncol 2011; 13:669-79

HIT-SKK 2000 for Medulloblastoma

von Bueren AO et al. Neuro-oncol 2011; 13:669-79

For M0 children with non-desmoplastic/non-nodular variants,For which predominantly local relapses lead to less favorablesurvival rates, local RT has been added after chemotherapy

SFOP Trial for Medulloblastoma

Maximal safe resection of primary tumor

3 courses given in 7 cyclesCourse 1: carboplatin

Course 2: etoposide and cisplatin

Course 3: vincristine and cyclophosphamide

For disease progression or relapse, salvage therapy

including high-dose chemotherapy, stem cell rescue and radiotherapy(involved field for M0,

involved or craniospinal field for M+)

Children < 5 years of ageN = 79

Grill J et al. Lancet Oncol 2005; 6:573-80

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Grill J et al. Lancet Oncol 2005; 6:573-80 Grill J et al. Lancet Oncol 2005; 6:573-80


For 64 pts without metastases at diagnosis, radiotherapy free-survivalat 3 and 5 years was 23% and 22%. Craniospinal-radiotherapy-freeat 3 and 5 years was 63% and 57%

Mean IQChemo alone 91HDCT + RT 72

Head Start I and II for Medulloblastoma

21 children < 6 years with M0 medulloblastoma

Dhall G et al. Pediatr Blood Cancer 2008; 50: 1169-75

Head Start I and II for Medulloblastoma

Dhall G et al. Pediatr Blood Cancer 2008; 50: 1169-75

4 treatment-related deaths

International Meta-Analysis

Rutkowski S et al J Clin Oncol 2010; 28:4961-8

Medulloblastoma (HIT-REZ 1997 & 2005)

Muller K et al. Int J Radiat Oncol Biol Phys 2014; 88:1019-24

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Craniospinal RT Dose (1800 cGy)

Goldwein JW et al. Int J Radiat Oncol Biol Phys 1996; 34:899-904

A prospective study from CHOP used 1800 cGy CSRT and 5580 cGy to the posterior fossa with 8 cycles of VCR, CCNU and CDDP in 10 children 18-60 mos 4-year survival was 69%No marked change in IQ scores among survivors

Indiana University study of 7 children (age 20-64 mos) treated with 4 mos of chemotherapy followed by 1800 cGy CSRT + 54 Gy PF boost3 patients relapsed (all outside PF)2 of 3 were salvaged4/6 survivors have endocrine deficitsAll 6 required special assistance in school

Jakacki RI et al. Int J Radiat Oncol Biol Phys 2004; 60:531-6

COG ACNS0031 Protocol

18 Gy 23.4 Gy

CTV = GTV + 1.5 cm

Mulhern RK et al. Lancet Oncol 2004, 5:399-408

Infant Studies in Ependymoma

Baby POG study: 1 and 2 year progression free survival rates were 58% and 42%

SFOP Ependymoma Study

73 children < 5 years of age underwent surgery and postoperative chemotherapy7 cycles of 3 courses alternating 2 drugs at each course: procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) for 1.5 yearsSalvage was reresection + local radiotherapy 4 year PFS was 22%

4 year OS was 59%4 year freedom from XRT: 23%

Grill J et al. J Clin Oncol 2001; 19:1288-96

Ependymona: Head Start III

19 children < 10 years of age with ependymoma treated with surgery followed by 5 induction chemo cycles and 1 consolidation cycle of myeloablative chemotherapy followed by autologous stem cell rescueXRT given to children 6-10 years and < 6 years with residual disease prior to consolidation3/3 supratentorial and 1/6 infratentorial had CR after induction chemotherapy

Venkatramani R et al. J Neurooncol 2013; 113:285-91

Ependymoma

St. Jude study of 88 children treated with 3D conformal RTDose 50.4 Gy (n = 15, all < 18 months) to 59.4 GyMedian age at RT: 2.85 yearsClinical target volume was tumor bed + residual tumor with a 10 mm margin. Planning target volume was CTV with a 3 to 5 mm margin


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Ependymoma


MGH Proton Ependymoma Study

70 children with localized ependymoma received postoperative involved field proton therapyMedian age: 38 months (range, 3 months to 20 years)73% had infratentorial tumors47% were anaplastic66% had gross total resectionMedian follow-up: 46 months

MacDonald SM et al. Neuro-oncology 2013; 15:1552-9





Different Types of Radiotherapy Technology

Intensity modulated radiation therapyProton therapyStereotactic radiosurgeryBrachytherapy

Three Dimensional, Conformal Radiotherapy

Gross Tumor Volume (GTV)Clinical Target Volume (CTV)Internal Target Volume (ITV)Planning Target Volume (PTV)

ICRU99

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Difference between 3D-CRT and IMRT

3D-CRT IMRT

INTENSITY MODULATED RADIATION THERAPY (IMRT)

Craniopharyngioma IMRT Intensity Modulated Radiation Therapy

IMRT in Medulloblastoma

Paulino AC et al. Cancer 2011; 117:635-41

N = 50

Ototoxicity and IMRT in Medulloblastoma

Huang E et al. IJROBP 2002; 52:599-605, Paulino AC et al. IJROBP 2010; 78:1445-50

Median follow-up(months)

Mean dose to cochlea

Mean cisplatin

Dose

Pediatric Oncology GroupOtotoxicity Grade

(number of patients)

Grade 0

Grade1

Grade2

Grade 3

Grade 4

Conventional RTN=11

51 54.2 Gy(53.2-55.8)

220mg/m2 (180-270)

2 2 0 6 1

IMRTN=15

18 36.7 Gy (23.4-50.8)

290mg/m2 (180-300)

6 4 3 1 1

IMRTN=88*

41 35.3 Gy(standard risk), 43 Gy (high risk)

300 mg/ m2

29 32 11 13 3

64%

13%

18%

* Number of ears

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IMRT in Pediatric Brain Tumors

First Author Tumor Type N Local Control Overall Survival

Paulino Medulloblastoma 50 90.5% (5yr) 72% (5yr)

Polkinghorn Medulloblastoma 33 84.8% (median:63 mos)

87-88% (median:63 mos)

Vieira Medulloblastoma 41 85.2% (median:44 mos)

90% (median:44 mos)

Schroeder Ependymoma 22 68% (3yr) 87% (3yr)

Paulino Low grade glioma 39 78.2% (8yr) 93.7% (8yr)

Greenfield Craniopharyngioma 24 90.7% (solid, 10yr)60.7% (cystic, 10yr)

96.0% (10yr

Merchant Craniopharyngioma 88 88.1 -96.2% (5yr) NA

Proton Therapy

Spread Out Bragg PeakProton CSI foMedulloblastoma r

Medulloblastoma and Protons

Thyroid

OrganMean

Dose (Gy)Maximum Dose (Gy)

Thyroid 0 4

Testis 0 0

Pituitary 24 24

Hypothalamus 25 30

Esophagus 9 25

Courtesy of Dr. Anita Mahajan

Proton Therapy for Craniopharyngioma

Photon Therapy for Craniopharyngioma

Courtesy of D. Grosshans

PROTONS IMRT

Posterior Fossa Ependymoma


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Protons in Pediatric Brain Tumors

First Author Tumor Type N Local Control Overall Survival

Bishop Craniopharyngioma 21 81% (3yr cystic) 96% (3yr)

MacDonald Ependymoma 70 83% (3yr) 95% (3yr)

McGovern AT/RT 31 Median progression-free survival: 20.8 mos

Median survival: 34.3 mos

MacDonald Germ cell tumor 22 100% (median:28 mos)

100%(median:28 mos)

Hug Low grade glioma 27 21/27 pts (median:3.3 years)

21/27 pts (median:3.3 years)

Int J Radiat Oncol Biol Phys 87(2), 2013

BRACHYTHERAPY

Method of radiotherapy in which sealed radioactive sources are used to deliver radiation at a short distance by interstitial, intracavitary or surface application. With this mode of radiation therapy, a high dose can be delivered locally to the tumor with rapid dose fall-off in the surrounding normal tissue

Commonly Used Brachytherapy Sources

Radionuclide Half-life Gamma ray energy

Physical configuration

Cesium-137 30 years 662 KeV Tubes, needles

Iodine-125 60 days 27-35 KeV Seeds, liquid

Iridium-192 74 days 0.136-1.06 MeV Wire, seeds

Palladium-103 17 days 20-23 KeV seeds

Radium-226 1622 years 0.017-2.44 MeV Tubes, needles

Brachytherapy Iodine-125 Seeds for Pediatric Low-Grade Glioma

Ruge MI et al. J Clin Oncol 2011; 29:4151-9

147 pts < 20 yrs treated with I-125 stereotactic brachytherapy30 day morbidity: 5.4%5- and 10-year overall survival rates were 93% and 82%21 (14.8%) relapsedComplete response in 24.6%, partial response in 31.0% and stable disease in 29.6%Tumor volume > 15 ml. associated with increased relapse

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Stereotactic Radiosurgery

The intersection of multiple arcs of radiation results in a high target dose while sparingnormal brain tissue.

Stereotactic Radiosurgery

One treatmentRadiobiologically more effective for more radioresistant tumors as high fraction size is deliveredHighly conformal form of treatmentCan be linear accelerator based or gamma knife

Size limitDoes not follow the 4Rs Principle of RadiobiologyIn children, screws to the developing skull may limit its useNeed neurosurgeon to put frameBrain and Head and Neck…although now there is SBRT

Stereotaticradiosurgeryusing a singleisocenter totreat 4 separatetargets withHELIOSinverseplanningsystem and120-leafMulti-leafcollimator

Other Radiotherapy Modalities

Heavy Particles other than ProtonIntraoperative Radiotherapy

RADIOTHERAPY IN INFANTS WITH BRAIN TUMORS

CURECOGNITIVE DEFICITENDOCRINOPATHYGROWTH RETARDATIONVASCULOPATHYSECONDARY MALIGNANCY

PEDIATRIC NEUROONCOLOGY TUMOR BOARD: PUBLIC ENEMY # 1

RADIATION ONCOLOGIST

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Conclusions

Rapid development of organs during infancy is a critical concern in radiation therapy of infant brain tumorsThere is accumulating evidence that a subset of infants with medulloblastoma and ependymoma will not need radiotherapyThere is a growing body of literature that children 1 to 3 years of age may be treated with localized, conformal radiotherapy

Conclusions

IMRT and proton therapy are currently being employed in the treatment of brain tumors. Current evidence indicate that local control rates are comparable to historical control with the possible reduction of late toxicity in the future

2.radiotherapy in infant brain tumors...7/1/2015 1 arnold c. paulino, m.d. professor of radiation...

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