Pediatric Medulloblastoma Nandinee Ganeshan

Pediatric Cancers • Embryonal tumours of the CNS account for approximately 20-30% of all cancers

seen in children less than 15 years of age .▫ Medulloblastomas are one of the most common subtypes (approx. 18% ).

 • Incidences of medulloblastomas:

▫ Occur in a higher ratio of boys than girls▫ Median age group of 6- to 8- years with diagnosed cases decreasing with age

(Fig. 1).  

Figure 1. Age-dependent frequency of the most common pediatric brain tumours in %. (Rickert, 2001)

Medulloblastomas• Medulloblastomas is a highly

malignant tumour of undifferentiated primitive neuroectodermal (PNET) originating in the posterior fossa.

• Classification of medulloblastoma tumors :

▫ classical medulloblastoma▫ desmoplastic/nodular

medulloblastoma▫ medulloblastoma with

extensive nodularity▫ anaplastic medulloblastoma▫ large cell medulloblastoma

Figure 2. Saggital section of a T1 weighted MRI scan showing a medulloblastoma arising from the inferior cerebellar vermis. B. Contrast enhanced characteristic of medulloblastomas, seen with gadolinium-ehanced T1 weighted MRI scan. (Tomlinson, 1992)

Clinical Presentation • Medulloblastomas show pattern of infiltration from the cerebellum to

surrounding structures. • Symptoms are reflective of cerebellar function and location.

▫ Unsteadiness and poor coordination▫ Raised intracranial pressure from obstructive hydrocephalus .

• Secondary symptoms :▫ Vomiting ▫ Diplopia▫ Ataxia▫ Papilledema

• Patients with wide spread disease present with more severe symptoms: ▫ Spinal cord compression ▫ seizures

Diagnosis & Staging

Diagnosis:

• Magnetic resonance imaging (MRI)• CT scan• Post-surgery biopsy• Magnetic resonance spectroscopy

Staging:

Chang’s staging system for medulloblastomas is utilised:▫ Characterised by tumor size (T) and extent of tumor spread (M).

Staging

• T1 describes tumors less than 3 cm, invading the fourth ventricle or cerebellar hemisphere

• T2 indicates tumors greater than 3 cm, involving one adjacent structure• T3a defines tumors greater than 3 cm involving two adjacent structures• T3b tumors exhibit features of T3a lesions but originate from or invade the

floor of the fourth ventricle• T4 tumors are greater than 3 cm and extends through the aqueduct

• M0: No evidence of metastasis• M1: Tumor cells found in cerebrospinal fluid• M2: Tumor beyond primary site but still within the brain• M3: Tumor dessimination of seeds in spine area• M4: Tumor spread to areas outside the CNS

Treatment • The treatment of medulloblastomas is conducted with a multi-modality

approach incorporating surgery, radiation therapy and chemotherapy.

• Surgery: ▫ Primary source of treatment

• Radiation Therapy (RT): ▫ Administered post-operatively ▫ Restricted to patient over three years of age due to harmful effects of

radiation on the immature nervous system. ▫ Role of RT defined by patient risk group (average and high).

• Chemotherapy: ▫ Primary impact of multi-agent chemotherapeutic approaches on children

under three years of age▫ Decreases the use of high dose radiation therapy to the neuraxis.

Simulation

• Prone

• Customized foam body cradle and plastic mask for face and shoulders (Fig. 3).

• Head position with the chin extended

Planning• Pre- and postoperative magnetic

resonance images fused with the planning CT scan.

Cranial Treatment Volume: • The treatment fields are comprised of

the primary tumour site and the cerebrospinal pathways.

• Beam arrangement: An opposed lateral technique utilising 6MV photons beams.

IMRT Planning:

• Five non-coplanar 6-MV photon fields• Utilises dynamic multi-leaf collimators• Inverse planning software

Figure 4. Patient treated with tumour bed intensity modulated radiation therapy (IMRT) boost. Prescription dose of 32Gy. Tumour bed (red), PTV (purple). (Paulino, 2010)

Radiation TherapyRadiation therapy regime

• Standard-risk patients: 18Gy- 23Gy to CSI and boost to posterior fossa to 36Gy and/or tumor bed to 54- 55.8Gy.

•  • High-risk patients: 36-39.6Gy to CSI and posterior fossa boost to 45 Gy

and/or TB boost to 55.8 Gy.  

IMRT vs. Conventional radiotherapy

• The use of an IMRT boost for medulloblastoma has reported lower levels of ototoxicity

 ▫ 47% of IMRT patients showed no hearing loss ▫ 82% of patients receiving conventional therapy developed ototoxicity.

Craniospinal Irradiation

• Conventionally patients receiving cerebrospinal irradiation (CSI) are treated with:

• A single posterior photon

beam which are matched at the cranial junction (Fig. 5).

• The treatment volume includes the entire spine with at least a 1 cm margin.

Figure 5. The gap plane is definedat midline, at the level where the spine photons are observed. (Phillips, 2004)

Craniospinal IrradiationElectrons:

• Large CSI dose is reported to have negative effects on growth and development later in life.

• Electron beams as an alternative to limit the exit dose from the spine field.

• Organs at risk from the exit beam : ▫ Heart, thyroid, breast,

gastrointestinal tract and lungs and bone marrow

• Electron energy ranged from 15 to 21 MeV

• Moving junction at cranial/spine field junctions

Figure 6. Shows the moving junction over the three day cycle. The lower electron field has a separate insert made for each day of the cycle, to maintain the gap with the upper electrons, and keep the lower level constant. (Phillips, 2004)

Organs at RiskOrgan at Risk Dose Tolerance

Optic chiasm 45 Gy

Optic nerve 45Gy

Brainstem 54Gy

Lenses 8Gy

Cochlea V55<5

Cochlea (IMRT) 40% of boost dose

Side Effects & Management

• Late Toxicities:▫ Neurocognitive impairment, hearing loss, endocrine dysfunction

and skeletal growth retardation.

Acute Toxicity Side Effect Management

Nausea Antiemetic prior to treatment

Skin ulcerations Topical creams/ dressing

Pituitary gland failure hormone substitution

chronic neuropathy

Reflection• Medulloblastomas is an embryonal tumour with a high incidence in

children aged <15 years.

• The treatment is conducted with a multi-modality approach incorporating surgery, radiation therapy and chemotherapy.

• Treatment modality is heavily dependent on tumour staging and risk group categorization.

• Advancements in technology have provided a wide arrange of treatment options to improve survival and reduce the long-term side effects.

• Due to the vulnerable developmental stage of patients the effect of radiation therapy in the long term neurological effects must be observed.

References • Carrie, C., Grill, J. et al. (2009). Online quality control, hyperfractionated radiotherapy alone and reduced

boost volume for standard risk medulloblastoma: long-term results of MSFOP 98. Journal of Clinical Oncology. 27(11): 1879-1883.

• Chang, E., Allen, P. (2002). Acute toxicity and treatment interruption related to Electron and photon craniospinal irradiation in pediatric Patients treated at the university of texas M. D. Anderson Cancer Center. International Journal of Radiation Oncology Biology Physics. 52(4): 1008-1016.

• Dhall, G. (2009). Medulloblastoma. Journal of Child Neurology. 24: 1418.

• Fossati, P., Ricardi, U., Orecchia, R. (2009). Pediatric medulloblastoma: Toxicity of current treatment and potential role of protontherapy. Cancer Treatment Reviews. 35(1): 79-96.

• Geyer J., Sposto R. et al. (2005) Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J ournal of Clinical Oncol ogy. 23 (30): 7621-31.

• Kombogiorgas, D., Puget, S. et al. (2011). Appraisal of the current staging system for residual medulloblastoma by volumetric analysis. Child’s Nervous System. 27: 2101-2106.

• Oyharcabal-Bourden, V., Kalifa, C. et al. (2005). Standard-risk medulloblastoma treated by adjuvant Chemotherapy followed by reduced-dose craniospinal radiation therapy: A french society of pediatric oncology study. J ournal of Clinical Oncology. 23(19): 4726- 4734.

• Packer, R., Gajjar, A. et al. (2006). Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. Journal of Clinical Oncology. 24(25): 4202- 4208.

  

References• Packer, R., Goldwein, J. et al. (1999). Treatment of Children With Medulloblastomas With Reduced-Dose

Craniospinal Radiation Therapy and Adjuvant Chemotherapy: A Children’s Cancer Group Study. Journal of Clinical Oncology. 17(7): 2127- 2136.

• Phillips, C., Willis, D. et al. (2004). A modified technique for craniospinal irradiation in children designed to reduce acute and late radiation toxicity. Australasian Radiology. 48: 188-194.

• Polkinghorn, W., Dunkel, I. et al. (2011). Disease Control and Ototoxicity Using Intensity-Modulated RadiationTherapy Tumor-Bed Boost for Medulloblastoma. International Journal of Radiation Oncology Biology Physics. 81(3): 15-20.

• Paulino, A., Mazloom, A. et al. Local control after craniospinal irradiation, intensity-modulated radiotherapy boost, and chemotherapy in childhood medulloblastoma. Cancer. 117(3): 635- 641.

• Paulino, A., Lobo, M. et al. (2010). Ototoxicity after intensity-modulated radiation therapy and Cisplatin-based chemotherapy in children with medulloblastoma. International Journal of Radiation Oncology Biology Physics. 78950: 1445-1450.

• Rickert, C. & Paulus, W. (2001). Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification. Child’s Nervous System. 17: 503-511.

• Rutkowski, S., Von Hoff, K. et al. (2010). Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta-Analysis. Journal of Clinical Oncology. 28(33): 4961-4968.

• Tomlinson, F., Scheithauer, B. et al. (1992). Topical Review Article: Medulloblastoma: I. Clinical, Diagnostic, and Therapeutic Overview. Journal of Child Neurology. 7(2): 142-155.