2. 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)
3. 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 Figure 2. Saggital section of a T1 weighted MRI
nodularity scan showing a medulloblastoma arising from the
inferior cerebellar vermis. B. Contrast enhanced
▫ anaplastic medulloblastoma characteristic of medulloblastomas, seen with
▫ large cell medulloblastoma gadolinium-ehanced T1 weighted MRI scan.
(Tomlinson, 1992)
4. 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
5. 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).
6. 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
7. 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.
8. Simulation
• Prone
• Customized foam body cradle and
plastic mask for face and shoulders
(Fig. 3).
• Head position with the chin extended
9. 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
Figure 4. Patient treated with tumour bed
technique utilising 6MV photons beams.
intensity modulated radiation therapy (IMRT)
boost. Prescription dose of 32Gy. Tumour bed
IMRT Planning: (red), PTV (purple). (Paulino, 2010)
• Five non-coplanar 6-MV photon fields
• Utilises dynamic multi-leaf collimators
• Inverse planning software
10. Radiation Therapy
Radiation 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.
11. 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 defined
at midline, at the level where the spine photons
are observed. (Phillips, 2004)
12. Craniospinal Irradiation
Electrons:
• 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 Figure 6. Shows the moving junction over the three
junctions 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)
13. Organs at Risk
Organ at Risk Dose Tolerance
Optic chiasm 45 Gy
Optic nerve 45Gy
Brainstem 54Gy
Lenses 8Gy
Cochlea V55<5
Cochlea (IMRT) 40% of boost dose
14. Side Effects & Management
Acute Toxicity Side Effect Management
Nausea Antiemetic prior to treatment
Skin ulcerations Topical creams/ dressing
Pituitary gland failure hormone substitution
chronic neuropathy
• Late Toxicities:
▫ Neurocognitive impairment, hearing loss, endocrine dysfunction and
skeletal growth retardation.
15. 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.
16. 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.
17. 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.
Notas do Editor
Embryonal tumours of the CNS account for approximately 20-30% of all cancers seen in children less than 15 years of age (Rieken, 2011). Medulloblastomas are one of the most common subtypes of malignant intracranial tumour constituting approximately 18% (Fossati, 2009). Incidences of medulloblastomas occur in a higher ratio of boys than girls and peaks at a median age group of 6- to 8- years with diagnosed cases decreasing with age, as demonstrated in Figure 1 (Rickert, 2001).
Medulloblastomas is a highly malignant tumour of undifferentiated primitive neuroectodermal (PNET) originating in the posterior fossa (Rieken, 2011).According to the 2007 WHO classification of the tumors of the central nervous system (Dhall, 2009), medulloblastoma has been classified into five distinct subgroups: Classical medulloblastomaDesmoplastic/nodular medulloblastoma, Medulloblastoma with extensive nodularityAnaplasticmedulloblastoma Large cell medulloblastoma
Clinical PresentationThe clinical presentation of medulloblastomas is reflective of the location of the tumor. Following a pattern of infiltration from the cerebellarvermis into the fourth ventricle or cerebellar hemispheres (Tomlinson, 1992). In most cases patients exhibit signs of unsteadiness and poor coordination which is consistent with the function of the cerebellum which controls walking, balance and fine motor coordination (Dhall, 2009; Tomlinson, 1992). Furthermore, due to the proximity of the fourth ventricle raised intracranial pressure from obstructive hydrocephalus is a primary consequence with a multitude of secondary symptoms including: Vomiting DiplopiaAtaxia PapilledemaIn addition, patients with wide spread disease present with more severe symptoms of cord compression from spread to the spinal cord or seizures from dissemination to the cerebral hemispheres (Dhall, 2009).
Diagnosis & StagingThe diagnosis and staging of medulloblastoma is crucial to provide a targeted treatment (Dhall, 2009). Diagnosis: Magnetic resonance imaging (MRI) with gadolinium primary tool for staging. CT scan Histological analysis from post-surgery biopsy Magnetic resonance spectroscopy- helps distinguish between post-irradiation necrosis from tumor progression.
The staging of medulloblastomas clinically was deemed inaccurate therefore the operativestaging system patterned after the TNM classification developed by Chang et al. is widely utilized (Kombogiorgas, 2011). Variables of the system include tumor size (T) and extent of tumor spread (M) (Kombogiorgas, 2011; Rutkowski, 2010). T1 describes tumors less than 3 cm, invading the fourth ventricle or cerebellarhemisphere T2 indicates tumors greater than 3 cm, involving one adjacent structure or partially filling the fourth ventricle T3a defines tumors greater than 3 cm involving two adjacent structures, either filling the fourth ventricle T3b tumors exhibit features of T3a lesions but originate from or invade the floor of the fourth ventricle and generally fill the space T4 tumors are greater than 3 cm and extend either through the aqueduct into the third ventricle or into the cervical canal. M0: No evidence of metastasisM1: Tumor cells found in cerebrospinal fluidM2: Tumor beyond primary site but still within the brainM3: Tumordessimination of seeds in spine areaM4: 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. New standards in treatment management with the introduction of chemotherapy and reduced-dose craniospinal regimes have improved event-free survival (EFS) to 65% to 80% at 5 years (Carrie, 2009). Surgery: Surgery alone is ineffective in treating medulloblastomas due to their tendency to recur both locally in the posterior fossa and in the whole central nervous system (Fossati, 2009). However, surgery is still recognized as the primary source of treatment followed by post-operative irradiation/chemotherapy regimes. Radiation Therapy: Radiation therapy in conjunction with other modalities has achieved high levels of tumour control (Packer, 2010). It is mainly administered post-operatively and restricted to patients above three years of age. Most patients diagnosed with the condition are still in the early stages of brain development therefore irradiation is delayed to reduce the harmful effects of cranio-spinal radiation on the immature nervous system (Dhall, 2009; Tomlinson, 1992). Therefore challenge remains to improve upon survival rates while minimizing treatment-related side effects.The role of radiation therapy also varies with the perceived risk group of patient, which are characterised by average or high risk (Packer, 1999).Average risk is defined by complete surgical resection or with only minimal residual disease (<1.5 cm), and without evidence of distant metastasis (M0) according to Chang staging system.Patients who do not fulfil average risk criteria or present with macroscopic disease at spinal (M2) or supratentorial (M3) level are deemed high risk. Chemotherapy: The introduction of, in most instances, concurrent chemo-radiation regimes have been utilised to decrease the use of high dose radiation therapy to the neuraxis (Packer, 1999). The primary impact of multiagent chemotherapeutic approaches has been for children under the age of three, with preliminary studies showing five-year DFS rates between 30% and 70% in patients treated with chemotherapy alone following total resection (Geyer, 2005).
Patient positioned prone for ease of access however if anaesthesia is required patient is positioned supine (Paulino, 2010). Customized foam body cradle and plastic mask for face and shoulders, as seen in figure 3.Head position, prone or supine, is with the chin extended to reduce dose from the spinal field that can exit through the mandible and mouth as it diverges (Phillips, 2004).
Using pre- and postoperative magnetic resonance images fused with the planning CT scan (Polkinghorn, 2011). Treatment volume: The treatment fields are comprised of the primary tumour site and the cerebrospinal pathways. The regions are treated concurrently rather than sequentially to minimize the risk of cells migrating from untreated to treated areas (Tomlinson, 1992). The whole-brain treatment volume extended to the entire frontal lobe and cribiform plate region. The boost volume included the entire posterior fossa with a 1 cm margin around the tentorium (Parker, 2006).An opposed lateral technique utilising 6MV photons beams are used to treat the cranial volume (Parker, 2006). For IMRT:A gross tumor volume (GTV) was outlined from the acquired CT image to which a 1.5cm margin in all directions is added to from the Planning tumour volume (PTV) (Polkinghorn, 2011). IMRT plans typically utilise a five noncoplanar 6-MV photon fields delivered using dynamic multileaf collimators calculated using inverse-planning software (Polkinghorn, 2011).
Radiation TherapyRadiation therapy regime for the various risk groups were outlined (Paulino, 2010; Oyharcabal-Bourden, 2005; Parker, 1999).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 therapyThe use of advanced techniques such as intensity modulated radiation therapy (IMRT) to irradiate the cranial volume in order to reduce treatment-related toxicity was evaluated The use of an IMRT boost in medulloblastoma has reported lower levels of ototoxicity in patients due to the increased conformity around the target volume and decreasing the high-dose region in surrounding normal tissue where the cochlea is situated (Polkinghorn, 2011; Paulino, 2011; Paulino, 2010). 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 in the prone position using standard immobilisation equipment.The spinal irradiation utilises a single posterior beam which are matched at the cranial junction of the opposed beams which can be clearly observed in Figure 5. The treatment volume includes the entire spine with at least a 1 cm margin at either side and with a 1 to 2 cm margin past the termination of the thecal sac (Parker, 2006; Chang, 2002).
Electron Beams: A large CSI dose is reported to have negative effects on growth and development later in life as most patients have not undergone pubescent growth. Organs at risk from the exit beam (due to the decreased separation in children) are: Heart, thyroid, breast, gastrointestinal tract and lungs and bone marrow (when large bone fields are treated) (Phillips, 2004).The use of electron beams has been investigated as an alternative to limit the exit dose from the spine field. Electron energy ranged from 15 to 21 MeV, depending on the coverage of the spine by the 90% isodose line (Chang, 2002; Phillips, 2004).Dose homogeneity at the cranial and spine junction area was managed by a moving junction. The size is constant but its position is moved by 1 cm daily over a 3 day cycle (Fig.) (Phillips, 2004).
Organs at Risk Reduction of the late effects of radiation therapy in children diagnosed with medulloblastoma is crucial due to the implication of improved survival rates and long term survival. Treatment-related side effects: neurocognitive impairment, hearing loss, endocrine dysfunction, and skeletal growth retardation (Polkinghorn, 2011). Dose constraints: optic chiasm 45 Gy, optic nerves 45 Gy, brainstem 54 Gy, cochlea V55 < 5 and lenses 8 Gy (Paulino, 2010). Dose constraint for the cochlea during IMRT planning is 40% of the IMRT boost dose.
Acute Toxicity/Side EffectManagement The acute effects of treatment were increased in severity with a chemo-radiation regime than radiation therapy alone (Rieken, 2011). However side effects can be managed by the appropriate health professional. Nausea- Antiemetic prior to treatmentSkin ulcerations-Topical creams/ dressingPituitary gland failure- hormone substitution chronic neuropathy Treatment-related side effects: neurocognitive impairment, hearing loss, endocrine dysfunction, and skeletal growth retardation (Polkinghorn, 2011). These effects are most often permanent manifest gradually in later life. Therefore, appropriate treatment must be prescribed to reduce long term effects.
Reflection Medulloblastomas is an embryonal tumour with a high incidence in children.The treatment is conducted with a multi-modality approach incorporating surgery, radiation therapy and chemotherapy.Treatment regime is 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.
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 Oncology. 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.
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 systemtumors 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.
