Medulloblastoma
BACKGROUND
Estimate the annual incidence of medulloblastoma (MB) in the U.S. What is its frequency relative to other CNS tumors in children?
~500 cases/yr of MB in the U.S. It is the 2nd most common pediatric CNS tumor (20% of cases; #1 is low-grade glioma at 35%–50%). It is the most common malignant brain tumor in the posterior fossa (PF) in children and adolescents, comprising 40% of all PF tumors.
What is the median age of MB at Dx?
MB has a bimodal age distribution, with a median age of ~7 yrs in children (peak incidence between 5 and 9 yrs) and ~25 yrs in adults.
Is there a sex predilection to MB?
Yes. Males are more commonly affected than females (2:1).
What is the cell of origin?
Neuroectodermal cells from the superior medullary velum (germinal matrix of cerebellum) or cerebellar vermis
MB is a subtype of what class of tumors?
MB is a subtype of embryonal tumors (along with PNET and atypical teratoid rhabdoid tumor [ATRT]).
Mutation of which gene distinguishes ATRT from MB?
Loss of INI1 distinguishes ATRT from MB. INI1 is found on chromosome 22 and functions as a tumor suppressor gene.
What % of pts present with CSF spread at Dx?
30%–40% of MB cases present with CSF spread at Dx.
For what MB age group is CSF spread more common?
This is more common in younger pts.
Does extra-axial spread occur in MB? If so, where?
Extra-axial spread is rare, but when it does occur it is typically to bone.
What are the characteristic histologic features and markers for MB?
MB appears as small round blue cells. 40% have Homer-Wright rosettes, and most stain + for neuron-specific enolase, synaptophysin, and nestin.
What are some other types of small round blue cell tumors?
Other small round blue cell tumors include:
1. Lymphoma
2. Ewing
3. Acute lymphoblastic leukemia
4. Rhabdomyosarcoma
5. Neuroblastoma
6. Neuroepithelioma
7. Medulloblastoma
8. Retinoblastoma
(Mnemonic: LEARN NMR)
What are the 3 histologic variants of MB?
Histologic variants of MB:
1. Classic
2. Nodular/Desmoplastic (better prognosis)
3. Large cell/Anaplastic (worse prognosis)
The desmoplastic histologic variant of MB is associated with what clinical features?
The desmoplastic variant is associated with:
1. LOH 9q
2. Older age at Dx
3. Better prognosis
What is the most aggressive histologic variant that also has a particularly high rate of CSF dissemination?
Large cell/Anaplastic is the most aggressive MB variant.
What % of MBs are familial, and what are some associated genetic syndromes?
2%–5% of MBs are familial. Associated genetic syndromes include Gorlin (PTCH1 mutation leading to nevoid basal cell carcinoma syndrome) and Turcot (APC mutation, also seen in colorectal cancer or familial adenomatous polyposis).
What are the common cytogenetic abnormalities in MB?
Common cytogenetic abnormalities in MB include:
1. Deletion of 17p (40%–50%)
2. Isochromosome 17q
3. Deletion of 16q
Where does MB most commonly arise?
Midline cerebellar vermis (75%), with the rest in cerebellar hemispheres
What is the DDx for a PF mass?
DDx for a PF mass includes:
1. MB
2. Ependymoma
3. ATRT
4. Astrocytoma
5. Brainstem glioma
6. Juvenile pilocytic astrocytoma
7. Hemangioblastoma
8. Mets
What are the 4 genetic MB subgroups and what mutations tend to occur in each subgroup?
1. WNT group: CTNNB1 mutation. Associated with Turcot. Least common (10%) subgroup.
2. SHH group: PTCH1, GLI3, MYCN. 30% of MB, often desmoplastic. Overrepresented in infants and adults (bimodal).
3. Group 3: MYC amplification, GABAergic expression. Enrich for large cell histology and are frequent mets at Dx.
4. Group 4: MYCN, CDK6 amplification
(Northcott PA et al., JCO 2011)
Describe the prognosis for each subgroup.
Good prognosis: WNT group and infants in SHH group
Intermediate prognosis: Group 4 and SHH group
Poor prognosis: Group 3
WORKUP/STAGING
What are some common presenting Sx for MB?
HA (nocturnal or morning), n/v, altered mentation due to hydrocephalus, truncal ataxia, head bob, and diplopia (CN VI)
To what are the common presenting Sx in MB?
Obstructive hydrocephalus/↑ICP (HA and vomiting) and cerebellar dysfunction
What symptoms would be expected with midline vs. lateral cerebellar tumors?
Midline tumors may cause gait ataxia or truncal instability (i.e., broad-based gate, difficulty with heel-to-toe), whereas tumors in the lateral hemispheres (more common in adults) may cause limb ataxia (i.e., dysmetria, intention tremor, difficulty with heel-to-shin). ATRT more likely to involve lateral hemispheres.
What is the “setting-sun” sign?
Downward deviation of gaze from ↑ ICP (CNs III, IV, and VI)
List the general workup for a PF mass at presentation.
PF mass workup: H&P (funduscopic exam, CN exam), CBC/CMP, MRI brain/spine, CSF cytology (may not be possible due to herniation risk), and baseline ancillary tests. Consider bone scan and CXR depending on presentation and risk factors.
What are some important ancillary tests to obtain prior to starting Tx?
Baseline audiometry, IQ testing, TSH, and growth measures
Is a tumor Bx necessary for Dx? Is a BM Bx necessary?
Per current COG MB protocol ACNS0331, a tumor Bx is unnecessary; pts often go straight to surgery. BM Bx is not part of the standard workup.
Is there any risk of CSF dissemination with shunt placement for MB?
No. There is no risk of CSF dissemination.
What tests should be obtained on days 10–14 postop?
MRI spine, CSF cytology. (Delay until day 10 to avoid a false+ result from surgical debris.)
When is MRI of the brain done? Of the spine?
MRI brain: preop and 24–48 hrs postop
MRI spine: preop or 10–14 days postop
What can be done before Tx to reduce ICP?
Ventricular drain or shunt, steroids, acetazolamide (Diamox)
List the T staging according to the modified Chang staging system for MB.
T1: <3 cm, confined
T2: ≥3 cm
T3a: >3 cm, with extension into aqueduct of Sylvius or foramen of Luschka
T3b: >3 cm, with unequivocal extension into brainstem
T4: >3 cm, extends beyond aqueduct of Sylvius or foramen magnum to involve 3rd ventricle/midbrain/upper cervical cord
List the M staging according to the modified Chang staging system for MB.
M0: no subarachnoid or hematogenous mets
M1: +CSF
M2: nodular intracranial seeding
M3: nodular seeding in spinal subarachnoid space
M4: extraneural spread (esp BM, bone)
Define standard-risk and high-risk MB.
Standard risk (two-thirds): >3 yo, GTR/NTR <1.5 cm2 residual, and M0
High risk (one-third): <3 yo or STR >1.5 cm2 residual, or M+
What may contribute to the poor prognosis of <3 yo?
Reduction in volume and/or dose or elimination of RT in very young children due to concerns of toxicity may contribute to the poor prognosis in this age group.
TREATMENT/PROGNOSIS
What is the most important prognostic factor at Dx for MB? What are other poor prognostic factors for MB?
M stage is the most important prognostic factor. Other poor prognostic factors include male sex, age <3 yrs, and unresectable Dz/STR.
What is the management paradigm for standard-risk MB?
COG approach: Standard-risk MB management: max safe resection → RT with concurrent weekly vincristine → adj chemo (8 6-wk cycles of cisplatin/CCNU/vincristine). RT is CSI to 23.4 Gy → cone down 1 (CD1) to PF to 36 Gy, then cone down 2 (CD2) to cavity/residual; or PF to 54–55.8 Gy; or cavity/residual to 54–55.8 Gy (MDACC).
What chemo regimens are typically used for MB?
Initial studies that established the efficacy of reduced-dose CSI (23.4 Gy) with chemo in standard-risk MB used concurrent vincristine with RT → adj cisplatin/CCNU/vincristine. The CCG A9961 trial recently found similar outcomes when cyclophosphamide was substituted for CCNU. (Packer R et al., JCO 2006 )
What is the management paradigm for high-risk MB?
High-risk MB management paradigm for pts >3 yo: same as standard risk, but the CSI dose is 36 Gy; also, nodular intracranial or spinal mets may to be boosted to 45–50.4 Gy depending on location (whether lesion is above or below spinal cord terminus).
For high-risk MB pts, what is the total boost dose for pts with intracranial (M2) vs. spinal (M3) mets?
Per COG ACNS0332, boost intracranial mets to 50.4 Gy, focal spinal mets below the cord terminus to 50.4 Gy, focal spinal mets above the cord terminus to 45 Gy, and diffuse spinal Dz to 39.6 Gy.
Estimate the 5-yr EFS for standard- and high-risk MB.
The 5-yr EFS for standard risk is ~80% and for high risk ~50%–60%.
What is the management paradigm for MB pts <3 yo?
MB pts <3 yo management paradigm: max safe resection → chemo until pt reaches 3 yo. At 3 yo, consider standard therapy with CSI → more chemo. If desmoplastic histology, consider omitting RT altogether. New protocols use surgical bed RT alone after induction chemotherapy in 18- to 36-mo patients.
What are the potential risks of aggressive surgery in the PF?
The major risk of aggressive surgery in the PF is PF syndrome (10%–15% of cases): mutism, ataxia, dysphagia, hypotonia, respiratory failure, and mood lability caused by disruption of the dentatorubrothalamic pathway to the supplemental motor cortex. PF syndrome typically presents 12–24 hrs postop and improves over several mos. Other potential complications include aseptic meningitis and CSF leakage.
In MB, how are NTR, STR, and “Bx only” defined?
NTR: <1.5 cm2 residual on postop MRI
STR: 51%–90% resection
Bx only:
In MB, is there a difference between NTR vs. GTR in terms of EFS? How about STR and GTR?
Retrospective studies suggest that pts who obtain an NTR and GTR have similar outcomes (Gajjar A et al., Ped Neurosurg 1996). However, 5-yr EFS is worse in STR pts (54%) compared to GTR/NTR pts (78%). (Zeltzer PM et al., JCO 1999)
What chemo agent improved DFS and OS according to MB studies in the 1990s?
Cisplatin. Prior to the introduction of cisplatin, several studies (SIOP I and CCG 942) failed to show improved OS with the addition of adj chemo.
What 2 studies demonstrated the need for chemo with reduced-dose CSI (23.4 Gy) for standard-risk MB?
There has been no RCT comparing reduced-dose CSI +/– cisplatin-based chemo. The need for cisplatin-based chemo is inferred from the following 2 studies:
1. POG 8631/CCG 923: randomized standard-risk MB to 36 Gy vs. 23.4 Gy CSI alone (no chemo). There was a trend toward ↓ EFS and OS in the 23.4-Gy arm. (Thomas PR et al., JCO 2000)
2. CCG 9892 (phase II): standard-risk MB treated with 23.4 CSI with concurrent weekly vincristine → 55.8-Gy boost to PF → adj cisplatin/CCNU/vincristine. 5-yr PFS was 79%, which was similar to historical controls treated with 36 Gy CSI and similar chemo. (Packer R et al., JCO 1999) Basis for POG A9961 reduced dose CSI.
Can RT be delayed for MB pts <3 yo by using chemo alone? What studies support this?
Yes. Given the toxicity of RT in pts <3 yo, it is reasonable to delay RT until 3 yo, especially with desmoplastic histology.
Baby POG (Duffner PK et al., Neurooncol 1999, NEJM 1993): <3 yo, 206 pts, high-/low-risk MB + other PNET, chemo alone (Cytoxan + Vincristine (VCR) × 2–> cisplatin + etoposide) × 2 yrs if <2 yo, × 1 yr if 2–3 yo. 5-yr OS was 40%, and PFS was 32%.
German BTSG data (Rutkowski S et al., NEJM 2005): <3 yo, 43 pts, high-/low-risk MB, chemo (Cytoxan, vincristine, methotrexate, carboplatin, VP-16, intrathecal methotrexate). 5-yr PFS was 58%, and OS was 66%. The majority of pts had a desmoplastic variant histology. The benefit was best in M0 pts (5-yr PFS of 68% and OS of 77%)
SFOP data (Grill J et al., Lancet Oncol 2005): <5 yo, 79 pts. 5-yr OS was best in R0M0 (73%) vs. 13% with M+.
What was the Tx regimen on COG A9934 for MB pts <3 yo?
Initial surgery → induction chemo × 4 mos with Cytoxan, vincristine, cisplatin, etoposide → 2nd surgery for identifiable or residual Dz → age/risk group/response-adapted conformal RT to PF + primary site (no CSI) → maintenance chemo × 8 mos. Enrolled children were older than 8 mos but younger than 3 yrs, all M0 MB.
Age/risk/response-adapted RT:
If <24 mos and CR: 18 Gy to PF → tumor bed boost to 50.4 Gy, or 54 Gy if PR/SD/+ residual
If >24 mos and CR or PR: 23.4 Gy to PF → tumor bed boost to 54 Gy
(Ashlet DM et al., JCO 2012)
What evidence supports the use of >50 Gy total doses in MB?
Retrospective data suggest that LC in the PF varies with dose above and below 50 Gy. In 60 MB cases, if the PF dose was >50 Gy, the LC was 79%. However, if the PF dose was <50 Gy, the LC was 33%. (Hughes EN et al., Cancer 1988)
In MB pts, does the entire PF need to be boosted to >50 Gy?
Retrospective evidence suggests that few failures occur in the PF outside the tumor bed (<5%).
Fukunaga-Johnson et al. reviewed 114 pts treated with CSI → boost to the entire PF. The solitary site of the 1st failure within the PF but outside the tumor bed occurred in 1 of 27 failures. (IJROBP 1998)
Wolden et al. reviewed 32 pts treated with tumor bed boost only. There were 6 total failures: 5 outside the PF and 1 within the PF but outside the boost volume. (JCO 2003)
Merchant et al. conducted a prospective phase II trial of 23.4 Gy CSI + PF boost to 36 Gy and primary site to 55.8 Gy with dose-intensive chemo. 5-yr EFS was 83%, and PF failure was 5%. Reduced doses to temporal lobes, cochlea, hypothalamus. (IJROBP 2008)
What are the RT technique questions being addressed in COG ACNS0331?
In ACNS0331, standard-risk pts 3–7 yo are randomized to CSI to 18 Gy vs. 23.4 Gy. For the 18 Gy arm, all pts got a PF boost to 23.4 Gy. All standard-risk pts 3–7 yo underwent a 2nd randomization: CD to 54 Gy to whole PF vs. tumor bed only. Standard-risk pts 8–22 yo: 23.4 Gy CSI → randomization to CD to 54 Gy to PF vs. tumor bed only.
What was the rationale for 18-Gy CSI in ACNS0331?
CSI doses in excess of 20 Gy still pose a significant risk for cognitive and growth outcomes, particularly in young children. Pilot study in 10 children with PNET of the PF showed comparable outcomes to higher doses. (Goldwein J et al., IJROBP 1996)
What question does ACNS0334 attempt to address?
Phase III trial in children <3 yrs with high-risk MB or PNET. Trial addresses the addition of high-dose MTX to the 4-drug induction chemo regimen of VCR, etoposide, cytoxan, cisplatin → 2nd surgery, consolidation, and peripheral blood stem cell rescue. RT is at the discretion of the institution.
Is there a role for pre-RT chemo in MB pts >3 yo?
No. In MB pts >3 yo, intensive chemo prior to RT (vs. RT then chemo) is associated with ↑ RT toxicity, RT Tx delays, and worsened RFS. (German HIT 91: Kortmann RD et al., IJROBP 2000)
What benefit does proton therapy have in the Tx of MB?
Retrospective data suggest that proton plans have ↓ dose to the cochlea/temporal lobe compared to IMRT (0.1%–2% vs. 20%–30%), and virtually no exit dose to the abdomen, chest, heart, pelvis. Recent study suggests less morbidity, including GI and heme toxicity (although this is in adults). (Brown AP et al., IJROBP 2013)
Is there a role for hyperfractionated RT to reduce cognitive sequelae of MB Tx?
MSFOP 98, a phase II trial, evaluated hyperfractionated RT in MB and showed promising results. 48 standard-risk pts were treated with CSI 1 Gy bid to 36 Gy → tumor bed boost 1 Gy bid to 68 Gy. 6-yr OS was 78%, and EFS was 75%. Decline in IQ appeared less pronounced than in historical controls. (Carrie C et al., JCO 2009)
How are MB pts simulated?
MB simulation: supine or prone, neck extended (so PA spine field does not exit through the mouth), head mask, shoulders positioned inferiorly (to allow for lat cranial fields). Depending on institutional experience, can simulate supine, which allows better airway access during anesthesia, most places are now doing supine technique.
What modalities of RT have been used for CSI?
Photons, electrons (at MDACC in years past), and protons are the more commonly used RT modalities for CSI therapy.
In CSI, which fields are placed 1st?
Spinal fields are placed 1st (to allow calculation of collimator angle for the cranial field based on spinal field beam divergence).
Cranial fields are placed 2nd (down to C5-6 or as low as possible but need to ensure laterals do not go through shoulder).
By what angle are the cranial field collimators rotated?
Arctan (one-half length of sup spine field/SSD), which matches the cranial field to the spine field divergence
What are the borders of the spine field(s)?
Superior: matched to cranial field
Inferior: end of thecal sac (near S2-3, check on sagittal spine MRI)
Lateral: 1 cm past pedicles (some centers plan with wider margins in sacrum to cover neural foramina)
By what angle is the couch kicked and in which direction?
Couch kick for CSI: arctan (one-half length of cranial field/source axis distance); couch kicked toward side treated to match cranial field divergence (for breast, kick is away)
What is a potential problem with a couch kick?
Couch could be rotated in the opposite direction than intended. At MDACC, treatments are usually planned without a couch kick to eliminate moving table in wrong direction. A small amount of overlap occurs lat to cord, but doses used are relatively low and amount of overlap is decreased by feathering the junction.
If multiple spinal fields are used, what is the skin gap? At what depth is the match?
With multiple spine fields, the skin gap = ([0.5 × Length 1 × d]/SSD1) + ([0.5 × Length 2 × d]/SSD2) where d is the depth of the match, which is typically at the ant cord edge.
How is “feathering” done? Why is it used?
There are several techniques, and feathering is dependent upon institutional experience. Feathering helps reduce hot and cold spots in plan. At MDACC, several techniques are used, including inter- and intrafractional junctioning for photons, electron junction technique, and proton junction technique.
Interfractional junctioning may be modulated with field-in-field technique and consists of moving junction superiorly 0.5 cm on 7th and 13th fraction. This creates 12 fields with junctions.
Intrafractional junctioning may be modulated with step-and-shoot technology. 3 junction control points at 1-cm gaps (i.e., 0, 1, and 2 cm with the use of multileaf collimators [MLCs]) are created, and each control point delivers one-third of the fractional dose. MLC leaves remain outside the field to ensure minimal interleaf leakage.
Where should the isocenter be placed in the cranial field for CSI? What cranial structure should be assessed for adequate coverage?
For the half-beam block technique, the isocenter should be placed behind the lenses to minimize divergence of beams into the opposite lens; the cribriform plate is not optimally visualized on conventional simulation films. A generous margin must be given in this area, or CT contours of the cribriform plate can be outlined to ensure coverage.
What CSI techniques can be employed if the entire spine cannot be included in 1 field?
The practitioner can increase the SSD (i.e., 100 cm → 120 cm) or rotate the collimator using a single field, but if the length is >36–38 cm, then 2 spinal fields are needed, with the inf field’s isocenter placed at the junction (using half-beam block to minimize the cold spot). Match at L1-2, as this is the area where the depth of cord changes the most.
TOXICITY
What is Collins’ law as it pertains to the max length of follow-up needed for pediatric tumors?
Defines period of risk for recurrence (age at Dx + 9 mos [gestational period]). If tumor was present in utero, then age at Dx + 9 mos determines rate of growth for it to become clinically evident. Residual Dz should become evident in same timeframe. (Sure U, Clin Neurol Neurosurg 1997)
What factors predict for greater decline in IQ after CSI?
Factors for decline in IQ after CSI:
Age <7 yrs (most important)
Higher dose (36 Gy vs. 23.4 Gy)
Higher IQ at baseline
Female sex
(Ris MD et al., JCO 2001)
For how long can the pt’s IQ decline after CSI?
>5 yrs. Hoppe-Hirsch et al. reviewed 120 MB pts treated with CSI to 36 Gy. At 5 yrs, 58% had an IQ >80. At 10 yrs, only 1% had an IQ >80. (Childs Nerv Syst 1990)
What are some important factors influencing IQ scores/neurotoxicity after RT?
Age at Tx with RT (most important), volume and dose of RT, and sex (female > male)
What is the dose constraint to the cochlea?
V30 <50% is the dose constraint to the cochlea (max is 35 Gy with chemo).
What is the most common hormone deficiency after RT to the brain? What is the dose threshold?
GH. The threshold dose for GH deficiency is ∼10 Gy.
What is the annual IQ drop after full PF boost in MB pts younger and older than 7 yrs? What structure is most important?
IQ drop of 5 points/yr if <7 yo and 1 point/yr if >7 yo. The dose to the supratentorial brain (temporal lobes) is most important.
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