Brain Tumors in Children

Transcription

1 Brain Tumors in Children Michael A. Grotzer University Children s Hospital of Zurich, Switzerland Incidence of Childhood Cancer CNS Tumors Acute lymphoblastic Leukemia Neuroblastoma Non-Hodgkin Lymphoma Wilms Tumor Hodgkin Lymphoma Acute myeloblastic Leukemia Rhabdomyosarcoma Retinoblastoma Osteosarcoma Ewing Sarcoma Others 0% 10% 20%

2 Prognosis of Pediatric Cancer 5-Year Survival Probability 100% 80% 60% 40% 20% Wilms Tumor ALL Osteosarcoma CNS Tumors 0% Years of diagnosis SEER (USA) Etiology of Childhood CNS Tumors: Hereditary Factors NF-1 astrocytomas (optic pathways) NF-2 schwannomas (vestibular, trigeminal), ependymomas, meningiomas Tuberous sclerosis cortical dysplasia (cortical tubers), subependymal nodules, subependymal giant cell astrocytomas Von Hippel-Lindau disease hemangioblastomas (cerebellar, ) Turcot syndrome medulloblastoma NBCC syndrome medulloblastoma Li-Fraumeni syndrome choroid plexus carcinoma, astrocytomas, medulloblastoma, ependymoma

3 Etiology of Childhood CNS Tumors: Ionizing Radiation Cranial irradiation for treatment of tinea capitis, leukemia, CNS tumors Radiation doses as low as 3 Gy Latency usually 5-25 years Most of these secondary CNS tumors classified as astrocytomas and meningiomas Etiology of Childhood CNS Tumors: Other Factors Endogenous immunosuppression Wiskott-Aldrich syndrome Ataxia teleangiektasia Exogenous immunosuppression Organ-transplant recipients HIV infection Polyomaviruses? SV40, JC, BK

4 Pediatric Brain Tumors Differ From Adult Brain Tumors Histology: The types of tumors encountered in children are uncommon in adults, and vice versa Localization: infratentorial > supratentorial Surgery: The value of extensive tumor resection has been confirmed for a variaty of childhood brain tumors Chemotherapy: has been shown to be effective in improving overall outcome in several childhood brain tumors is increasingly used to delay or avoid using radiotherapy in children younger than 3 years of age AT/RT Medulloblastoma Pilocytic Astrocytoma female male Ependymoma Diffuse Astrocytoma WHO II Glioblastoma Age (years)

5 Survival by Age for Malignant Brain Tumors Population Survival Probability Ages 0-19 Ages Ages Ages 60+ Years since diagnosis SEER (USA) Technical Advances in Imaging and Neurosurgery

6 Irradiation Using Protons Protons Photons Energy Photons Distance Protons Ependymoma: Incidence and Epidemiology Frequency: 10-15% of all childhood CNS cancers Prevalence: 1 in 28,000 live birth (USA) Median age: 6 years No known predisposing exposures

7 Ependymoma: Localization Posterior fossa > supratentorial extraventricular > lateral ventricles > spinal The majority of tumors are localized at the time of diagnosis The primary tumor site remains the most likely area of disease relapse Pathology and Grading Ependymoma WHO II Anaplastic Ependymoma WHO III microvascular proliferation high mitotic activity

8 Ependymoma: Prognostic Factors positive negative Total resection Less than total resection Age over 4-6 years Age under 4-6 years Local XRT > 45 Gy Local XRT < 45 Gy Differentiated (WHO II) Anaplastic (WHO III) 6.9 years old, focal seizures

9 Localized Ependymoma >4 Years of Age STOP Surgery: No residual OP no residual tumor tumor Conformal Irradiation WHO II WHO III CP VP16 CP VP16 CP VP16 CP VP16 CP VP16 8 months Merchant TE et al. Lancet Oncol 2009 n=153 median age 2.9 years Conformal radiotherapy (59.4 Gy, 10 mm margin) after definitive surgery

10 0.8 years old, head tilt (5 weeks), vomiting (2 weeks) Localized Ependymoma <4 Years of Age Residual Tumor <15 months OP CP VP16 CP VP16 MTX MTX CP VP16 MTX MTX CP VP16 Protonbeam Irradiation weekly CP VP16 CP VP months 3 months

11 14 months later Irradiation Using Protons Protons Photons Energy Photons Distance Protons

12 Anesthesia

13 Patient immobilization

14 Appropriate patient safety system

15 Medulloblastoma Before Surgery Radio local Chemo 5-Year Survival 0% 0% Since 1940 local + cs 50% Since % 80%

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17 Medulloblastoma: Treatment for Children > 3 Years (Packer RJ, 1994) S U R G E R Y RADIATION Posterior fossa 54 Gy Craniospinal 36 Gy Cisplatin Lomustine Vincristin week

18 Longterm Effects of Current Medulloblastoma Therapy Growth dysfunction Endocrine dysfunction Hearing loss Alopecia Risk for second malignancies Social and emotional problems Intellectual deficits Late Effects in Pediatric Brain Tumor Survivors: Interplay of Different Factors Therapy Tumor Patient RT total dose direct tissue effects development status RT dose rate RT treatment volume indirect mechanical effects genetic predisposition tissue sensitivities RT dose distribution compensating mechanisms other therapy

19 HIT-SKK`92 Medulloblastoma Age <3 years / hdmtx Carbo/VP / hdmtx Carbo/VP / hdmtx Carbo/VP CCR End of Therapy MTX i. ventr. MTX i. ventr. MTX i. ventr. no CCR <18 Months >18 Months experimental Chemo craniospinal Radiation Rutkowski S et al. N Engl J Med 2005 HIT-SKK` No RT Survival Probability ± ± ± 0.15 no residual tumor residual tumor solid metastases n=17 n=14 n= Years Since Diagnosis Rutkowski S et al. N Engl J Med 2005

20 Intensity-Modulated Radiotherapy (IMRT) 54.2 Gy 64 % auditory apparatus radiation WHO grade 3/4 hearing loss (n = 26 medulloblastoma) 36.7 Gy (-32%) 13 % Huang E et al. Int J Radiat Oncol Biol Phys 2002 Irradiation Using Protons Energy Photons Protons Photons Protons Distance

21 Medulloblastoma Staging: Modified Chang Classification System M1 Tumor cells in CSF M2 Nodular seeding in cerebellum, cerebral subarachnoid space, or in 3 rd or 4 th ventricles M3 Nodular seeding in spinal subarachnoid space M4 Extraneuraxial metastasis Patient Stratification S U R G E R Y Clinical Factors + Molecular Phenotype Low Risk: Minimal Therapy Standard Risk: Maximal Therapy High Risk: Novel Therapies

22 c-myc β-catenin 1.00 Low c-myc (n=13) Progression-free Survival Probability High c-myc (n=13) Overall Survival Probability Nuclear accumulation (n=27) No accumulation (n=81) p= Years Since Diagnosis Grotzer, Clin Cancer Res 2001 p=0.015 Years Since Diagnosis Ellison, J Clin Oncol 2005 Classic MB (64-83%) composed of sheets of small uniform cells with a high nuclear-to cytoplasmatic ratio Anaplastic MB medulloblastoma with extensive nodularity (3%) contains pleomorphic Desmoplastic cells MB with (7%) polyhedral combines forms and nodules a high of differentiated growth neurocytic cells with a low growth fraction. Abundant apoptosis and fraction and desmoplastic internodular examples of cell wrapping are evident zones of moderately pleomorphic cells with a high growth fraction Infants (favourable prognosis) and adults Gilbertson Gilbertson & Ellison & Ellison Annu Annu Rev Pathol Rev Pathol Mech Mech Dis 2008 Dis 2008

23 Nodular/desmoplastic medulloblastoma combines nodules of differentiated neurocytic cells with a low growth fraction and desmoplastic internodular zones of moderately pleomorphic cells with a high growth fraction Anaplastic MB (10-22%) contains pleomorphic cells with polyhedral forms and a high growth fraction. Abundant apoptosis and examples of cell wrapping are evident Large-cell MB (2-4%) contains groups of large uniform cells with vesicular nuclei and a single nucleolus. Anaplasia characterizes other regions of this variant Gilbertson & Ellison Annu Rev Pathol Mech Dis 2008 Localized Medulloblastoma <4 Years of Age HIT 2000 Carbo VP-16 Carbo VP-16 CR + desmoplastic / extensive nodular OP / hdmtx CARBO / VP-16 MTX i. ventr. / hdmtx CARBO / VP-16 MTX i. ventr. / hdmtx CARBO / VP-16 MTX i. ventr. Radiotherapy 54 Gy conformal no CR CIS CCNU CIS CCNU CIS CCNU CIS CCNU <18 months CIS CCNU CIS CCNU CIS CCNU CIS CCNU Radiotherapy 54 Gy conformal

24 Medulloblastoma are molecularly distinct from spnet and AT/RT Pomeroy SL et al. Nature 2002 Atypical Teratoid/Rhabdoid CNS Tumor (AT/RT) Mutation/deletion of the tumor suppressor SMARCB1 (INI1) WHO % Burger P, Am. J Surg Pathol 1998 Number of cases Age (years) female male Survival 80% 60% 40% 20% 0% Months after diagnosis

25 AT/RT Boston Protocol DFCI V: Vincristine P: Cisplatin D: Doxorubicin C: Cyclophosphamide E: Etoposide A: Dactinomycin i.th.: MTX, Cytarabin, Hydrocortisone 2-year Overall Survival: 70 ± 10% Chi S et al. JCO 2008 Unsupervised hierarchical clustering of human 1.0 exon array expression data from 103 primary medulloblastomas using 1,450 high standard deviation genes Northcott P A et al. JCO 2010

26 10% 30% 25% 35% Nuclear β-catenin Oncogenes, Tumor Suppressors, and Key Cytogenetics Northcott PA et al. (2012) Nat. Rev. Neurol.

27 Therapeutic Targets of WNT Medulloblastomas Low risk None of the WNT targeted therapies have shown benefits in MB Therapies that target mutated TP53 are not in regular use for MB therapy Mouse model of WNT MB developed Current strategy: de-escalation not large cell/anaplastic c-myc/mycn not amplified β-catenin nuclear pos. residual tumor 1.5 cm 2 OP Radiotherapy 23.4 Gy craniospinal 54 Gy local PNET5 CIS CCNU CIS CCNU 6 months CIS CCNU Standard risk all others all without profile OP Radiotherapy 23.4 Gy craniospinal 54 Gy local PNET6 CIS CCNU CIS CCNU CIS CCNU CIS CCNU ± CARBOPLATIN 8 months SIOP PNET Study Group Therapeutic Targets of SHH Medulloblastomas GDC-0449 IPI-026 LDE225 <3 years + >14 years of age Desmoplastic / nodular subtype Somatic mutations in PTCH1/2, SMO, or SUFU High-level amplification of the SHH effectors, GLI1/2 Germline mutations of SUFU (young children), PTCH1 (Gorlin syndrome) SMO antagonists GDC-0449, IPI-926, LDE225,

28 SMO Inhibitor Treatment in an Adult with Metastatic MB Rudin CM et al. N Engl J Med 2009 after 2 months of therapy with GDC-0449 after 5 months of therapy with GCD-0449 SMO Inhibitor Treatment in an Adult with Metastatic MB Rudin CM et al. N Engl J Med 2009 after 2 months of therapy with GDC-0449 after 5 months of therapy with GCD-0449

29 SMO Inhibitor Treatment in an Adult with Metastatic MB Rudin CM et al. N Engl J Med 2009 after 2 months of therapy with GDC-0449 after 5 months of therapy with GCD-0449 Hh activation Pre Screening TMZ naive children and adults who have relapsed after RT (n=69) TMZ pretreated children and adults who have relapsed after RT OR RT naive ± TMZ children 6 years old (n=40) Randomization 2:1 LDE225 QD TMZ, QD x 5 every 28 days LDE225 QD LDE225 QD Optional Cross-over to LDE225 QD confirmed PD Post Treatment FollowUp Primary endpoints: ORR Secondary endpoints: DoR, PFS, safety, OS, QoL

30 LDE225 (200 mg QD): Responses in Medulloblastoma Pre-treatment: surgery, irradiation, 4 chemotherapy regimens and HDCT Partial response maintained for 4 months Therapeutic Targets of Group 3 Medulloblastomas Owing the pharmacological difficulty of targeting a a transcription factor, small molecule inhibitors of MYC have not yet achieved wide success or acceptance in the clinic Studies on other rationally chosen targets for Group 3 have not yet been described Mouse model available Current strategy: intensification Therapeutic Targets of Group 4 Medulloblastomas The underlying biology of Group 4 tumors is less well understood Mouse model not yet available Current strategy:??

31 MB Metastases and Primary Tumors are Distinct XH Wu et al. Nature 2012 Conclusions Patient subgroup status will become an integral component of prospective clinical trials This will enable the use of treatment protocols that are rationally tailored towards each subgroup of the disease Methods to verify patient subgroup affiliation will continue to evolve Targeting primary tumor targeting metastasis