Radiation Oncology: A Question-Based Review


John P. Christodouleas and Ori Shokek

image Background

Estimate the annual incidence of medulloblastoma (MB) in the U.S. What is its frequency relative to other CNS tumors in children?

~400 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%).

What is the median age of MB at Dx?

MB has a bimodal age distribution, with a median age of ~7 yrs in children and 25 yrs in adults.

Is there a gender predilction to MB?

Yes. Males are more commonly affected than females (2:1).

What is the cell of origin?

Neuroectodermal cells from the sup 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).

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:

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

3.     Large cell/Anaplastic

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?

5% of MBs are familial. Associated genetic syndomes include Gorlin (PTCH mutation) and Turcot (APC mutation).

What are common cytogenetic abnormalities in MB?

Common cytogenetic abnormalities in MB:

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 posterior fossa (PF) mass?

DDx for a PF mass:

1.     MB

2.     Ependymoma

3.     Astrocytoma

4.     Brainstem glioma

5.     Juvenile pilocytic astrocytoma

6.     Hemangioblastoma

7.     Mets

image Workup/Staging

What are some common presenting Sx for MB?

HA, n/v, altered mentation due to hydrocephalus, truncal ataxia, head bob, and diplopia (CN VI)

To what are common presenting Sx due in MB?

Obstructive hydrocephalus/↑ICP (HA and vomiting)

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

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 are some important ancillary tests to obtain prior to starting Tx?

Baseline audiometry, IQ testing, TSH, and growth measures

What tests should be obtained on days 10–14 postop?

MRI spine, CSF cytology. (Delay to day 10 to avoid a false+ result from surgical debris.)

When is MRI of the brain done? Of the spine?

1.     MRI brain: preop and 24–48 hrs postop

2.     MRI spine: preop or 10–14 days postop

What can be done before Tx to reduce ICP?

Ventricular shunt/drain, steroids, acetazolamide (Diamox)

Is there a risk of CSF dissemination with shunt placement?

No. There is no risk of CSF dissemination with shunt placement.

List the T staging according to the modified Chang staging system for MB.

1.     T1: ≤3 cm, confined

2.     T2: >3 cm, partial fill of 4th ventricle, invades 1 adjacent structure

3.     T3a: invades 2 adjacent structures, complete fill of 4th ventricle

4.     T3b: extends into brain stem, arises from floor of 4th ventricle, complete fill of 4th ventricle

5.     T4: 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.

1.     M0: no mets

2.     M1: +CSF

3.     M2: nodular seeding intracranially

4.     M3: nodule in subarachnoid space in cord

5.     M4: extraneural spread

Define standard-risk and high-risk MB.

1.     Standard risk: >3 yo, GTR/NTR <1.5 cm2 residual, and M0

2.     High risk: <3 yo or STR >1.5 cm2 residual, or M+

image 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 gender, age <3 yrs, and unresectable Dz/STR.

What is the management paradigm for standard-risk MB?

Standard-risk MB management paradigm: 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 → CD1 to PF to 36 Gy, then CD2 to cavity/residual or PF to 55.8 Gy.

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 need to be boosted to 39.6–50.4 Gy depending on location.

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.

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, and mood lability caused by disruption of the dentorubrothalamic 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?

1.     NTR: <1.5 cm2 residual on postop MRI

2.     STR: 51%–90% resection

3.     Bx only: <50% resection

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).

The introduction of what chemo agent improved DFS and OS according to MB studies from 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)

Can RT be delayed for MB pts <3 yo by using chemo alone? What studies support this?

1.     Yes. Given the toxicity of RT in pts <3 yo, it is reasonable to delay RT until 3 yo, especially with desmoplastic histology.

2.     Baby POG (Duffner PK et al., NEJM 1993): <3 yo, 206 pts, high-/low-risk MB + other PNET, chemo alone × 2 yrs if <2 yo, × 1 yr if 2–3 yo. 2-yr OS was 45%, and PFS was 35%.

3.     German 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.

4.     French 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 is the Tx regimen on COG A9934 for MB pts <3 yo?

Initial surgery → induction chemo × 4 mos → 2nd surgery for identifiable or residual Dz → age/risk group/response-adapted conformal RT to PF + primary site (no CSI) → maintenance chemo × 8 mos

Age/risk/response-adapted RT:

1.     If <24 mos and CR: 18 Gy to PF → tumor bed boost to 50.4 Gy, or 54 Gy if PR/SD/+ residual

2.     If >24 mos and CR or PR: 23.4 Gy to PF → tumor bed boost to 54 Gy

What evidence supports the use of >50 Gy total doses in MB?

Retrospective data suggests that LC in the PF varies with dose above and below 50 Gy. Hughes et al. reviewed 60 MB cases and found that if the PF dose was >50 Gy, the LC was 79%. However, if the PF dose was <50 Gy, the LC was 33%. (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 1/27 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)

What are the RT technique questions being addressed in COG protocol 0331?

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 get a PF boost to 23.4 Gy. All standard-risk pts 3-7 yo undergo a 2nd randomization: CD to 55.8 Gy to PF vs. tumor bed only. Standard-risk pts >8 yo: 23.4 Gy CSI → randomization to CD to 55.8 Gy to PF vs. tumor bed only.

Is there a role for pre-RT chemo in MB pts >3 yo?

No. In MB pts >3 yo, intensive chemo prior to RT is associated with ↑ RT toxicity, RT Tx delays, and worsened RFS. (German HIT 91Kortmann RD et al., IJROBP 2000)

What benefit does proton therapy have in the Tx of MB?

Retrospective data suggests 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.

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: prone, neck extended (so PA spine field does not exit through the mouth), shoulders positioned inferiorly (to allow for lat cranial fields)

In CSI, which fields are placed 1st?

1.     Spinal fields are placed 1st (to allow calculation of collimator angle for the cranial field based on spinal field beam divergence).

2.     Cranial fields are placed 2nd (down to C5-6 or as low as possible).

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)?

1.     Superior: matched to cranial field

2.     Inferior: S3

3.     Lateral: 1 cm past pedicles (wider in sacrum)

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

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?

At the Johns Hopkins Hospital, 0.5-cm gap shifts/day (for a total 1.5 cm over 3 days). Feathering helps reduce hot and cold spots in plan.

How do field edges and isocenters of respective fields move with feathering?

There are many techniques; however, at the Johns Hopkins Hospital, the following technique is typically used:

1.     Cranial fields: isocenter is fixed, lower jaw moves

2.     Spinal fields: isocenter and inf jaw moves

Where should the isocenter be placed in the cranial field for CSI? What cranial structure should be assessed for adequate coverage?

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 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.

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 mo [gestational period])

image Toxicity

What are some long-term toxicities of CSI + boost?

↓Growth (↓GH), ↓IQ, ototoxicity, hypopituitarism, and 2nd malignancy

What factors predict for greater decline in IQ after CSI?

Factors for decline in IQ after CSI:

1.     Age <7 yrs (most important)

2.     Higher dose (36 Gy vs. 23.4 Gy)

3.     Higher IQ at baseline

4.     Female gender

(Ris MD et al., JCO 2001)

For how long can the pt's IQ decline after CSI?

>5 yrsHoppe-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 gender (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.