Pediatric Malignant

Gliomas

MD. Yan Carlos Vargas Caycho

MR Radiation Oncology Edgardo Rebagliati Martins Hospital

Lima - PERU

Pediatric CNS Tumors Gliomas

Low-Grade Gliomas

Astrocytomas

Cerebellar Astrocytoma

Optic Pathway Gliomas

Oligodendroglioma

High-Grade Gliomas

Brainstem Gliomas

Pediatric CNS Tumors No Gliomas

Ependymoma

Embryonal Tumors

Intracranial Germ-Cell Tumors

Craniopharyngioma

Choroid Plexus Tumors

CNS Lymphoma

Meningioma

Neuronal Tumors

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

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.

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

Histopathology

• Glioblastoma multiforme (GBM),

• Anaplastic Astrocitoma (AA)

• Anaplastic oligodendrogliomas (AO),

• Anaplastic mixed gliomas (AMG)

anaplastic variants of

• pleomorphic xanthoastrocytoma,

• ganglioglioma, and

• pilocytic astrocytoma.

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

ALTERACIONES GENÓMICAS EN GLIOMAS DIFUSOS DEL ADULTO

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.

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.

Diagnostic Imaging

Diagnostic Imaging

Treatment

Currently,

combination of

surgery,

radiation,

and chemotherapy

is the standard therapy for children

with high-grade gliomas

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) .

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

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

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

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.

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.

Chemotherapy

The effectiveness of adjuvant chemotherapy

in conjunction with radiation

for high-grade glioma

is

uncertain

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

Chemotherapy

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

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.

RADIATION ONCOLOGY TEAM Edgardo Rebagliati Martins National Hospital

Lima - PERU