O estado da arte da Radioterapia nos gliomas de alto grau

IV Encontro de Residentes em RadioterapiaMódulo 4 - Pediatria

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Introdução

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Gliomas de alto grau são TU primários do SNC

quase sempre fatais. Recentes descobertas no

tratamento tem prolongado a vida destes

pacientes. A cura, no entanto, permanece

improvável para a maioria.

Kun LE et al. Supratentorial brain tumors. Halperin, Pediatric Radiation Oncology

Incidência

Kun LE et al. Supratentorial brain tumors. Halperin, Pediatric Radiation Oncology

Incidência de Gliomas de alto grau foi 0,85 per 100.000

nos EUA entre os anos de 2004 – 2008 Central Brain Tumor

Registry of the United States (CBTRUS)

Pacientes com Gliomas de alto grau no entanto, tem

prognóstico reservado com uma SVG em 5 anos:

GBM = < 20%AA = 30 – 40 %

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Etiologia e Epidemiologia

Merchant T. E. et al. CNS tumor brain in Children in Gunderson, Clinical Radiation Oncology 4

O fator causal é DESCONHECIDO.

Exposição prévia à radiação.

Fatores genéticos e hereditários:

sd. LI – FRAUMENI

sd. TURCOT NEUROFIBROMATOSE tipo I

SD. LI – FRAUMENI

SD. TURCOT NEUROFIBROMATOSE tipo I

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Slide 4

1 (supressao do p53)mac; 15/05/2013

2 (polipose coloretal x TU SNC)mac; 15/05/2013

3 (desordem autossomica dominante)mac; 15/05/2013

Histologia

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Gliomas de Alto grau:

ASTROCITOMAS ANAPLÁSICOASTROCITOMA SUBEPENDIMAL DE CELS. GIGANTESOLIGODENDROGLIOMA ANAPLÁSICOOLIGOASTROCITOMA ANAPLÁSICOXANTOASTROCITOMA ANAPLÁSICOGANGLIOGLIOMA ANAPLÁSICO

GBM

GIII

G IV

Merchant T. E. et al. CNS tumor brain in Children in Gunderson, Clinical Radiation Oncology

Características Biológicas e Moleculares

Gliomas de alto grau pediátricos diferem em características genéticas e moleculares dos adultos:

Adultos Crianças

CODELEÇÃO 1p19q � Oligodendroglioma SV�

MGMT � Sensibilidade à QT SV�

IDH-1 IDH-2 � Gliomas de bxo grau SV�

p53 � Mutação

EGRF � Amplificado

p53 � Mutação

PDGFRA � Amplificado + COMUM > 3 ANOS

MGMT

Merchant T. E. et al. CNS tumor brain in Children in Gunderson, Clinical Radiation Oncology

EGRF

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3435

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Slide 6

33 Among the numerous focal genetic alterations elucidated in pediatric HGG, platelet-derived growth factor receptor A (PDGFRA) amplification is by far the most com- mon genomic event identified. This amplification seems to occur most often in older children and may have some prognostic signif- icance (Bax et al., 2010; Paugh et al., 2010; Qu et al., 2010)mac; 20/05/2013

34 Another mutation observed in about 10% of pediatric HGG is the V600E point mutation in BRAF (Nicolaides et al., 2011). Interestingly, this seems to be associated with tumors that also possess PDGFRA amplification (Jones et al., 2012). Distinct from the BRAFV600E mutation in many LGG, however, CDKN2A/CDKN2B mutations are more common in these HGG which may help explain why these lesions behave more malignant compared to their LGG counterparts (Jones et al., 2012).mac; 20/05/2013

35 Mutations in the p53 pathway are a much more common finding in pediatric HGG. Both overexpression of p53 and mutations in the TP53 sup- pressor gene can lead to defects in this pathway and tumorigenesis. mac; 20/05/2013

36 One of the most common genetic abnormalities in adult HGG is the ampli- fication of epidermal growth factor receptor (EGFR; Libermann et al., 1985; Barker et al., 2001). Although overexpression of the EGFR protein is sometimes seen in pediatric supratentorial HGG, the genetic amplification is quite rare (Libermann et al., 1985; Bre- del et al., 1999).mac; 20/05/2013

37 These data again highlighted the growing wealth of information supporting the distinctness between adult and pediatric HGG (Paugh et al., 2010). This group also did not identify a significant number of isocitrate dehydrogenase I (IDHI) mutations in pediatric HGG which have been shown to be quite prevalent and prognostic among adult HGG patients (Horbinski et al., 2009; Labussiere et al., 2010; Paugh et al., 2010).mac; 20/05/2013

Diagnóstico e Manejo

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� Tomografia computadorizada

� Ressonância magnética

Espectroscopia

- Perfil metabólico de determinada área.

- Progressão X Pseudo-progressão.

N-acetil-aspartato aumentado (NAA) � Sugere atividade tumoral

Merchant T. E. et al. CNS tumor brain in Children in Gunderson, Clinical Radiation Oncology

Diagnóstico e Manejo

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RECIDIVAS OCORRERAM EM UMA MARGEM DE 2 CM DO SÍTIO PRIMÁRIO

Hochberg e Pruitt et al.Usaram TC para determinar o local de recidiva de 90% dos GBM

• Área central de baixa captação, correspondendo a necrose.

• Área peritumoral de alta captação, correspondendo a proliferação TU.

• Área de baixa captação mais externa correspondendo ao edema vasogênico.

Merchant T. E. et al. CNS tumor brain in Children in Gunderson, Clinical Radiation Oncology

Tratamento

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A maior ressecção possível com déficit neurológico aceitável. (Neuronavegação)

PCTS > 36 MESES � RT com dose 59,4 Gy - 60 Gy.PCTS < 36 MESES � QT intensiva.

QT concomitante e/ou adjuvante.

Merchant T. E. et al. CNS tumor brain in Children in Gunderson, Clinical Radiation Oncology

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Slide 9

9 Radiation therapy has become the main- stay of therapy, particularly for those children older than 3 y/o with newly diagnosed HGG. Since younger children are more susceptible to the negative deleterious effects associated with radiation therapy and they seem to harbor more indolent tumors, they are often treated with chemotherapy alone and radiation- sparing approaches (Geyer et al., 1995; Duffner et al., 1996; Dufour et al., 2006; Sanders et al., 2007). For older children, focal radiotherapy with a margin around the tumor bed has become the standard. Previous studies have shown that there is no role for whole brain radiotherapy in patients with localized HGG (Buck- ner et al., 2007). Typically, the conventional dosing for a child with a newly diagnosed HGG is 50–60 Gy delivered in daily fractions of approximately 180–200 cGy over a 6 week period. Alternative radiotherapy techniques such as hyper- and hypo-fractionation have not consistently proven to be statistically beneficialin chil- dren with HGG and are typically not utilized outside of a clinical trial setting (Fallai and Olmi, 1997).mac; 20/05/2013

Radioterapia

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IMRT

RadiocirurgiaBraquiterapia

Conformacional

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Slide 10

24 Radiation therapy has become the main- stay of therapy, particularly for those children older than 3 y/o with newly diagnosed HGG. Since younger children are more susceptible to the negative deleterious effects associated with radiation therapy and they seem to harbor more indolent tumors, they are often treated with chemotherapy alone and radiation- sparing approaches (Geyer et al., 1995; Duffner et al., 1996; Dufour et al., 2006; Sanders et al., 2007). For older children, focal radiotherapy with a margin around the tumor bed has become the standard. Previous studies have shown that there is no role for whole brain radiotherapy in patients with localized HGG (Buck- ner et al., 2007). Typically, the conventional dosing for a child with a newly diagnosed HGG is 50–60 Gy delivered in daily fractions of approximately 180–200 cGy over a 6 week period. Alternative radiotherapy techniques such as hyper- and hypo-fractionation have not consistently proven to be statistically beneficialin chil- dren with HGG and are typically not utilized outside of a clinical trial setting (Fallai and Olmi, 1997).mac; 20/05/2013

Int. J. Radiation Oncology Biol. Phys.2006. 11

Análise retrospectivaJan/01 – Dez/03- 58 pacientes com glioma de alto grau- 70% GBM

IMRT 59,4 – 60 Gy 1,8 – 2 Gy/dia

Conformacional 3D – Conformacional

IMRT

X

CTV 1 - (T2 ou FLAIR) + margens 2 cm � 40 - 50 Gy - 1,8-2 Gy/diaCTV 2 - GTV + margens 2-3 cm � 10 - 20 Gy - 1,8-2 Gy/dia** PTV � 0,3 - 0,5 cm

12Int. J. Radiation Oncology Biol. Phys.2006.

IMRT reduziu as doses em medula (16%), nervo ótico (7%) e olho (15%) em relação ao tratamento 3D

Int. J. Radiation Oncology Biol. Phys.2006. 13

O tratamento com IMRT leva à redução da dose em orgãos de risco.

Não há diferença significativa entre as duas técnicas em relação a

cobertura do alvo.

AA – 5,6 meses GBM- 2,5 meses

AA – 36 mesesGBM – 9 meses

Follow up 24 meses:

JCO 2005. 14

Objetivo: Avaliar eficácia do FRST no tratamento de resgate de Gliomas

SV TOTAL: GBM 21 meses GIII 50 meses

SV pós FRST: GBM 8 mesesGIII 16 meses

PFS pós FRST: GBM 5 mesesGIII 8 meses

FRST: dose média 36 Gy (15 – 62 Gy)172 pcts com gliomas recorrentes: GBM 59

G III 42

FRST foi bem tolerada e pode ser efetiva no tratamento de recidivas

GBM 10 meses

Tempo médio entre o primeiro tratamento é o de resgate: GBM 10 meses G III 32 meses

Wernick et al. CANCER 2005. 15

- FOLLOW UP: 13 meses

- SV APÓS SRS: 10 meses

- PFS APÓS SRS: 7 meses

- SV TOTAL MÉDIA: 22 meses

SV 1 ano : 90%

SV 2 anos: 49 %

SV 3 anos: 26 %

32 pcts com GBM recidivado (36 lesões).Submetidos a tratamento padrão.

PFS médio após 1º tratamento: - 10 meses - Dose média: 15 Gy (10 -20 Gy) - Tratamento foi bem tolerado

Radiocirurgia estereotáxica é um tratamento efetivo na recidiva de GBM em pacientes selecionados

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FSRT

36 Gy

Resultados favoráveis no caso de recidiva TU com toxicidade aceitável.

SRS

10 - 20 Gy

Wernick et al. CANCER 2005 , JCO 2005

Análise retrospectiva, avaliando o uso do GliaSite como boost no tratamento inicial de GBM.

-20 pcts (39-76 anos)

-kps 80 %

-Ressecção máxima + GliaSite (50 Gy), seguido de RT externa com uma dose de 60 Gy, atingindo dose acumulada de 110Gy.

SV média 11,4 meses.

3 pacientes apresentaram toxicidade GIII

Int. J. Radiation Oncology Biol. Phys. 2006 17

Tumori. 2011;97(5):614-9. 18

GliaSite na recidiva de Gliomas de alto grau após nova cirurgia.

15 pcts (21-71 anos)

Kps ≥ 70 %

45 Gy (1cm)

Tratamento

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GliaSite – Radiation Therapy System

Estudos sugerem que é uma opção possível.É segura e de promissora eficácia, contudo apresentou

associação à necrose cerebral.Int. J. Radiation Oncology Biol. Phys.2006. Tumori. 2011;97(5):614-9.

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Slide 19

39 Radiation therapy has become the main- stay of therapy, particularly for those children older than 3 y/o with newly diagnosed HGG. Since younger children are more susceptible to the negative deleterious effects associated with radiation therapy and they seem to harbor more indolent tumors, they are often treated with chemotherapy alone and radiation- sparing approaches (Geyer et al., 1995; Duffner et al., 1996; Dufour et al., 2006; Sanders et al., 2007). For older children, focal radiotherapy with a margin around the tumor bed has become the standard. Previous studies have shown that there is no role for whole brain radiotherapy in patients with localized HGG (Buck- ner et al., 2007). Typically, the conventional dosing for a child with a newly diagnosed HGG is 50–60 Gy delivered in daily fractions of approximately 180–200 cGy over a 6 week period. Alternative radiotherapy techniques such as hyper- and hypo-fractionation have not consistently proven to be statistically beneficialin chil- dren with HGG and are typically not utilized outside of a clinical trial setting (Fallai and Olmi, 1997).mac; 20/05/2013

20Vernimmen FJ et al. Stereotactic proton beam therapy of skull base meningiomas. Int J Radiat Oncol Biol Phys. 2001;49(1):99-105.Bolsi A, et al. Radiotherapy of small intracranial tumours with different advanced techniques using photon and proton beams: a treatment planning study.

Radiother Oncol. 2003;68:1-14.. Bjo ̈rk-Eriksson et al. Taylot and francis 2005.

Toxicidade

Regressão Tumoral

Paugh, JCO 2010.21

Existem CARACTERÍSTICAS GENÉTICAS E MOLECULARES

DISTINTAS entre Glioma de alto grau pediátrico e adulto

com possíveis implicações no PROGNÓSTICO

PDGFRA pode ser usado como alvo no desenvolvimento de

novas terapias.

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Slide 21

12 PDGRFA AMPLIFICADO E GANHO DO CROMOSSOMO 1q ocorreu com alta frequência em TU radioinduzidos, sugerindo uma relação com a GLIOMAGENESE na infancia. mac; 20/05/2013

13 Patients and MethodsWe conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for 53 tumors. Results were compared with publicly available data from adult tumors.ResultsSignificant differences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregu- lated PDGFR signaling in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showed minimal copy number changes.ConclusionIntegrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFR may be a useful target for pediatric HGG, including diffusepontine gliomas.mac; 20/05/2013

28 There is data in a small number of cases showing that infant HGG appear to lack HOXA9/HOXA10 which are thought important for self-renewal (Jones et al., 2012). HOXA9/HOXA10 have been asso- ciated with more malignant variants with poor prognosis in some adults and older children with HGG (Jones et al., 2012). This may help explain why these young children with HGG have seemingly less aggressive disease. In a prospective French study evaluating the use of chemotherapy in young children less than 5 y/o with newly diagnosed HGG, 5-year PFS was 35%and 5-year OS was 59%, with a median follow-up of 5.2 years (Dufour et al., 2006). In a sepa- rate retrospective study performed at St. Jude Research Hospital reviewing the clinical characteristics and survival in children under 3 y/o with HGG, 5-year event-free survival (EFS) and OS were 28.6 and 66.3%, respectively (Sanders et al., 2007). These outcomes are far superior to those published in older children with HGG again suggesting that these tumors may be distinct (Finlay et al., 1995; Broniscer and Gajjar, 2004; Cohen et al., 2011). Other groups have shown this same phenomenon whereby younger children have an improved survival outcome even when utilizing radiation-sparing treatment strategies(Geyer et al., 1995; Duffner et al., 1996). It is unclear, however, if it truly is a specific age that is prognos- tic or if younger children simply develop HGG tumors that have unique biologic and molecular characteristics that confer a better prognosis. mac; 23/05/2013

Direções Futuras

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A implementação da PROTONTERAPIA no

tratamento de Gliomas de alto grau

pediátricos e a investigação de novas

CARACTERÍSTICAS GENÉTICAS E

MOLECULARES desse tipo de TU poderão

levar a melhores resultados em

tratamentos futuros.

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2021

Slide 22

18 ary efficacy analysis showed encouraging PFS (Lai et al., 2008). There are also ongoing studies evaluating the use of BVZ in chil- dren with newly diagnosed HGG as well, including the currently open COG ACNS-0822 trial. This trial is a randomized Phase II/III trial whereas patients with newly diagnosed HGG will be assigned to one of three chemo-radiotherapy arms, including vorinostat(a histone deacetylase inhibitor) given concurrently with radiation, temozolomide given with radiation, or BVZ given with radiation. All three arms are followed by the same maintenance chemother- apy combination of BVZ and temozolomide (ClinicalTrials.gov, 2010–2012b). This trial is currently accruing patients.mac; 20/05/2013

19 In adult HGG, the use of bevacizumab (BVZ), an anti- angiogenic agent that blocks vascular endothelial growth factor (VEGF), has shown promising results and a survival benefit in patients with recurrent HGG (Narayana et al., 2009; Huylebrouck et al., 2012; Morris, 2012). These findings led to the development of a pediatric trial within the PBTC-022 utilizing BVZ and CPT- 11 in children with recurrent CNS tumors, including a HGG and diffuse intrinsic pontine glioma (DIPG) strata (Gururangan et al., 2010). Thirty-one evaluable patients received a median oftwo courses of BVZ plus CPT-11. There were no sustained responses in either HGG or DIPG. Median time to progression was 127 days for HGG patients and 6-month PFS was 41.8%. Although the reg- imen was well-tolerated, it showed minimal efficacy in children with recurrent HGG (Gururangan et al., 2010).mac; 20/05/2013

20 In a study by Finlay et al. (2008), 27 chil- dren with recurrent malignant astrocytomas received myeloabla- tive chemotherapy followed by autologous marrow rescue with thiotepa and etoposide-based chemotherapy regimens. Five of 27 children survived event-free from 8.3 to 13.3 years at the time of publication. Another study by Guruangan et al. (1998) evalu- ated the outcome of myeloablative chemotherapy and autologous bone marrow rescue with or without radiotherapy in children younger than 6 years of age with a variety of recurrent malignant braintumors who had not previously received irradiation. Twenty patients with recurrent brain tumors were enrolled. Ten of 20 (50%) patients, including three patients with HGG were alive and disease free at a median of 37.9 months at the time of publication. They concluded that myeloablative chemotherapy with autologous hematopoietic cell rescue followed by additional external-beam irradiation appeared to be an effective retrieval therapy for some young children with recurrent brain tumors (Guruangan et al., 1998). These data suggest again that there may be a sub- group of children with recurrent HGG for which this strategy is appropriate.mac; 20/05/2013

21 Immune therapies, including vac- cine therapies are being increasingly utilized in both adult and children with newly diagnosed and recurrent HGG (Okada et al., 2003, 2007). Many of these trials in pediatrics are still ongoing with results forthcoming (ClinicalTrials.gov, 2005–2010, 2010–2012a).mac; 20/05/2013

Conclusões

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Gliomas de alto grau são menos comuns na população

pediátrica comparada à adulta, contudo responde por alta

morbidade e mortalidade.

Crianças < 3 anos: O padrão é atrasar a RT com QT até o paciente atingir 36 meses, evitando maior toxicidade.

Crianças > 3 anos: CX, RT e QT.

Recidiva: considerar reirradiação (SRS / FSRT).

Braquiterapia: papel ainda indefinido

Radioterapia com 59,4 – 60 Gy (3D ou IMRT)

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Slide 23

22 One specific targeted therapy that has shown promising pre-clinical data is poly ADP ribose polymerase (PARP) inhibitors. PARP1 is a protein involved in single-strand DNA break repair. Increased PARP1 expression has been observed in HGG as com- pared to non-neoplastic brain tissue. PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy (van Vuurden et al., 2011). Currently, there are ongoing trials in pediatric HGG exploring the use of PARP inhibitors in children with both newly diagnosed and recurrent HGG and DIPG (ClinicalTrials.gov, 2009–2012b, 2012). Many of the data on specific agents is forthcoming, and some experts suggest their role may be best suited as maintenance therapy in the setting of minimal residual disease (Herrington and Kieran, 2009). Another novel approaches to HGG treatment is convection- enhanced delivery (CED). CED utilizes a surgical technique to place a catheter locally and directly into the tumor or tumor resection cavity and directly infuses agents such as chemother- apy, cytotoxic proteins and other biologically targeted agents under a positive pressure gradient (White et al., 2012a,b). Tri- als utilizing this technique in children with HGG are ongoing (ClinicalTrials.gov, 2006–2012, 2009–2012a).mac; 20/05/2013

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