Yan Carlos Vargas Caycho Pediatric Malignant Gliomas Radioterapia en Gliomas de Alto Grado en Pediatria Radioterapia en Glioblastoma Multiforme Radioterapia en Astrocitoma Anaplasico Radioterapia en Tumores del Sistema Nervioso Central

1. Pediatric Malignant
Gliomas
MD. Yan Carlos Vargas Caycho
MR Radiation Oncology
Edgardo Rebagliati Martins Hospital
Lima - PERU

2. Pediatric CNS Tumors Gliomas
Low-Grade Gliomas
Astrocytomas
Cerebellar Astrocytoma
Optic Pathway Gliomas
Oligodendroglioma
High-Grade Gliomas
Brainstem Gliomas

3. Pediatric CNS Tumors No Gliomas
Ependymoma
Embryonal Tumors
Intracranial Germ-Cell Tumors
Craniopharyngioma
Choroid Plexus Tumors
CNS Lymphoma
Meningioma
Neuronal Tumors

5. High Grade Gliomas
WHO low-grade (WHO grade I and II) and high-
grade (WHO grade III and IV) astrocytomas.
poor outcome, and 5-year survival less than 20%.
Astrocytomas 40–50% of all pediatric tumors.
HGG in children are relatively
infrequent less than 20% of cases

6. High Grade Gliomas
High-grade astrocytomas:
Anaplastic astrocytoma (AA; WHO grade III) and
Glioblastoma (GBM, WHO grade IV),
only 15–20% of all pediatric brain tumors
Malignant gliomas represent 6.5% of all newly
diagnosed childhood intracranial neoplasms.

7. High Grade Gliomas
Links:
Prior radiation exposure (Pettorini et al. 2008)
Genetic syndromes:
Neurofibromatosis type 1 (NF1),
Turcot syndrome,
mutations in the APC gene and
mismatch repair genes hMSH2, hMLH1,and hPMS2.
Li–Fraumeni syndrome
mutations in the tumor suppressor gene p53

8. Histopathology
• Glioblastoma multiforme (GBM),
• Anaplastic Astrocitoma (AA)
• Anaplastic oligodendrogliomas (AO),
• Anaplastic mixed gliomas (AMG)
anaplastic variants of
• pleomorphic xanthoastrocytoma,
• ganglioglioma, and
• pilocytic astrocytoma.

9. Molecular Biology
Pediatric high-grade gliomas differ adult
despite histological similarities.
Molecular features identify
adult primary (de novo) GBM
secondary (progressive) GBMs lower-grade gliomas.
epidermal growth factor receptor (EGFR)
amplification ,
and tensin homolog ( PTEN ) mutations,
The latter occur in younger adults and have p53 mutations
platelet-derived growth factor receptor- a (PDGFR).
amplifi cation and overexpression

10. ALTERACIONES GENÓMICAS EN GLIOMAS DIFUSOS DEL ADULTO

11. Molecular Biology
Pediatric high-grade gliomas
frequent mutations in the tumor-suppressor gene p53 ,
poor outcome
Children with low p53 expression had a 5-year progression-free survival
(PFS) rate of 44% compared to 17% in patients with p53 overexpression
(Pollack et al. 2001, 2002a )
EGFR amplification (Bredel et al. 1999)
PTEN mutations (Nakamura et al. 2007)
are less frequent.

16. Clinical Features
These signs and symptoms may be nonspecific,
intracranial pressure,
Nonspecifi c symptoms include:
headache, nausea, and vomiting.
or those directly related to the location of the tumor.

17. Diagnostic Imaging

18. Diagnostic Imaging

19. Treatment
Currently,
combination of
surgery,
radiation,
and chemotherapy
is the standard therapy for children
with high-grade gliomas

20. Surgery
Gross total resection (GTR) is linked to longer survival
(Finlay et al. 1995 ; Heideman et al. 1997 ; Wolff et al. 2002) .
In the CCG 945 study, children with high-grade gliomas who underwent
GTRs (defined as >90%), had a 5-year PFS rate of
35% (±7%) compared to
17% (±4%) in the group that had subtotal resections (STR) ( p = 0.006)
AA patients who underwent
GTRs had a 5-year PFS rate of 44% (±11%) compared to
22% (±6%) for those who had STRs [ p = 0.055].
GBM patients who underwent
GTRs had a 5-year PFS rate of 26% (±9%) compared to
4% (±3%) for those who had STRs [ p = 0.046]
(Wisoff et al. 1998) .

21. Radiation Therapy
adjuvant therapy
improve survival of children with brain tumors
after surgical resection for older children
due to the invasive nature of HGGs, high local
failure rate after surgery, and morbidity with
more extensive surgery in the brain.
Fangusaro J,Warren KE. Unclear standard of care for pediatric high grade glioma
patients. J Neurooncol (2013) 113:341–2. doi:10.1007/s11060-013-1104-8

22. Radiation Therapy
50–60 Gy of external beam radiation
daily fractions of 1.8–2.0 Gy
majority of clinical trials using a dose of 54 Gy in 30 fractions
three-dimensional reconstructions using CT or MRI
Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, et al. Temozolomide
in the treatment of high-grade gliomas in children: a report from the Children’s
Oncology Group. Neuro Oncol (2011) 13:317–23. doi:10.1093/ neuonc/noq191

23. Radiation Therapy
Hyperfractionation
dose intensification by dose escalation (to a cumulative total
dose of 72 Gy) have failed to improve outcome in the setting
of highgrade gliomas
Hyperfractionated
Doses of radiation per fraction (usually 1–1.1 Gy)
administered more than once daily.
while limiting long-term side effects.
Fallai C, Olmi P. Hyperfractionated and accelerated radiation therapy in central
nervous system tumors (malignant gliomas, pediatric tumors, and brain
metastases). Radiother Oncol (1997) 43:235–46. doi:10.1016/S0167-
8140(96)01897-X

28. Radiation Therapy
Every patient in our study received adjuvant RT with a median dose for
the whole cohort and all subgroups of 59.4 Gy.
Interestingly, for the subgroup of patients with incomplete resection,
radiation dose at or above the median dose of 59.4 Gy did show a
significant improvement in PFS and OS in the grade IV patients.
The higher dose of radiation remained significant for improved OS .
As a result of STR, these patients are at higher risk for local recurrence.
Therefore, it is attractive to speculate that escalation of local therapy
could offer improvement in outcomes.
As suggested by our findings, it may be prudent to escalate the dose to
at least 59.4 Gy for grade IV patients who are unable to achieve a GTR.

40. Radiation Therapy
Long-term side effects
neurocognitive decline,
vasculopathies,
Endocrine abnormalities,
secondary malignancies.
The effects of radiation are particularly harmful to
the developing brain, and therefore the aim of
postsurgical therapy has been to limit the use of
radiotherapy in children less than 3 years of
age.

41. Chemotherapy
The effectiveness of adjuvant chemotherapy
in conjunction with radiation
for high-grade glioma
is
uncertain

42. Chemotherapy
In addition, the value of temozolomide with RT
has not been clearly established with
randomized data in pediatric HGG, despite
frequent use based on extrapolation from
benefit seen with adult glioblastoma

43. Chemotherapy

44. TEMOZOLAMIDE
TMZ induces DNA methylation of guanine
at O6 position, 7-methylguanine, 3-
methyladenine
Efficient BER system functions and
repairs DNA lesions in normal and tumor
cells

47. Conclusions
In children greater than 3 years of age,
surgery, radiation, and adjunctive chemotherapy.
For the younger child (less than 3 years of age),
the goal is to delay radiation therapy with chemotherapy
regimens to avoid significant side effects of radiation on the
developing brain.

49. RADIATION ONCOLOGY TEAM
Edgardo Rebagliati Martins National Hospital
Lima - PERU