Neurologic Oncology

ASTROCYTOMAS

Parisa Momtaz

Thomas J. Kaley

Epidemiology/Risk Factors

Grade 4 astrocytoma, glioblastoma multiforme, is the most common malignant 1° brain tumor, accounts for >50% of all gliomas
Has been a/w type 1 neurofibromatosis, Turcot syndrome, LFS
Polymorphisms in the CDKN2B & RTEL1 genes have been a/w greater risk
Ionizing radiation

Clinical Manifestations

Sx related to mass effect, parenchymal infiltration, hydrocephalus, tissue destruction
HA (most common, 35%), sudden onset, more sev. in the AM
Associated nausea, vomiting, focal neurologic deficits
Seizures (30%), more common w/low-grade tumors

Treatment Principles

Surgery

Goal is to obtain histologic dx, reduce mass effect while preserving neurologic function, debulking; can be curative for benign tumors
Stereotactic bx, open bx (primarily for tumors in critical areas where resection would lead to neurologic deficit)
Debulking procedure, subtotal resection, maximal resection
Post-op MRI should be obtained w/in 24-72 h to document extent of disease following surgery

EBRT: EBRT w/partial brain radiation is standard; is as effective as whole brain radiation while preserving nl brain tissue & reducing late neurotoxic effects
Re-irradiate if progression free for >2 y since last RT, the new lesion is outside the target of the last RT, size of recurrence is small
Complications: Radionecrosis (presents as a focal mass lesion w/contrast enhancement & mass effect), radiation-induced leukoencephalopathy (mos to y after, presents as diffused ↑ T2/FLAIR signal abnl on MRI w/assoc atrophy)

Chemotherapy

Most commonly used agent is temozolomide as it penetrates the blood-brain barrier
Nitrosoureas (eg, carmustine, lomustine), platinum-based therapies
Procarbazine, Lomustine, Vincristine (PCV) for oligodendroglial tumors
Limited benefit; used in combination w/surgery & radiation

Other therapeutic agents

Corticosteroids, anticonvulsant agents, anticoagulation meds

Pathology/Grading Classification

WHO classification as a four-tiered grading system based on key histologic features: ↑ cellularity, mitoses, endothelial proliferation, necrosis

Grade 1

Typically benign. Eg, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma
Well circumscribed, rarely transform to higher grade astrocytomas, are often resectable, & typically cured by surgery alone & if incomplete resection can successfully tx w/RT

Grade 2: Low-grade Astrocytomas

Diffuse infiltrating low-grade tumors w/only ↑ cellularity
Poor Px factors: Age ≥40 y, tumor ≥6 cm, tumor crossing midline, presence of neurologic deficit prior to resection
Typically are nonenhancing, low attenuation lesions on CT & MRI therefore T2-weighted or FLAIR MRI scans are preferred
Poorly circumscribed, invasive & can transform to higher grade astrocytomas (50% pts will undergo anaplastic transformation in 5 y)
Median survival is approx. 5 y
Tx:
- Surgery w/gross total excision w/o compromising function
- No consensus on the timing of EBRT. Standard radiation dose is 45-54 Gy.
- Limited data for temozolomide as adjuvant Rx.
- Acceptable regimens for recurrence/progressive disease include temozolomide, nitrosourea, PCV (procarbazine, lomustine, vincristine) & platinum-based Rx (Shaw EG, Neuro Oncol 2008;10:884)
Follow-up: MRI q3-6 mos for 5 y & then annually as late recurrences are common

Grade 3: Anaplastic Astrocytomas

Presence of mitoses distinguishes anaplastic from low grade
Can be both contrast enhancing & noncontrast enhancing on MRI
High propensity to undergo transformation to glioblastoma multiforme
Median survival 24 mos
Tx:
- Maximum surgical debulking w/o compromising function
- Adjuvant RT prolongs survival
- Adjuvant chemotherapy role unclear; single-agent carmustine & PCV have shown prolonged survival in some series & meta-analysis, temozolomide
- Recurrence: Temozolomide (Yung WK J Clin Oncol 1999;17:2766) & nitrosourea-based regimens

Grade 4: Glioblastoma Multiforme

Most common & most malignant of the 1° brain tumors
Onset of sx is abrupt & due to mass effect
Pathologic features: ↑ cellularity, endothelial proliferation, tumor necrosis
EGFR amp & Mt or loss of PTEN are characteristic
T1-weighted MRI scans w/the use of gadolinium show a ring-enhanced mass
Tx:
- Surgery followed by adjuvant RT w/concurrent & adjuvant temozolomide (Stupp R NEJM 2005;352:987)
- Bev monotherapy approved for recurrence

Figure 21-1 GBM TI post-contrast MRI MSKCC. Courtesy of Dr. T. Kaley

Figure 21-2 Low-grade Astrocytoma T2 FLAIR MSKCC. Courtesy of Dr. T. Kaley

OLIGODENDROGLIOMAS

Elizabeth Won

Thomas J. Kaley

Epidemiology

Incidence 3 per 1000000 in US
Rare subtype, 6-10% of all 1° CNS tumors
Typically seen in fourth to fifth decades; low-grade tumors occur at earlier age

Etiology and Clinical Manifestations

IR exposure, FHx of brain tumors, epilepsy/seizures, mutagen senility,
A/w genetic syndrome: Neurofibromatosis-1, tuberous sclerosis, RB1, Li-Fraumeni, & Turcot syndrome
S/S: Depend on extent & location of tumor. Seizures are frequently a/w oligodendroglioma. Median duration of onset of sx to dx is 6-17 mos.

Pathology

Morphology:
- Low-grade tumors: “Fried egg” appearance seen on paraffin but not frozen section
- High grade (anaplastic oligodendroglioma): High cell density, mitosis, nuclear atypia, microvascular proliferation, & necrosis
Molecular biology:
- 1p/19q codeletion seen in 60-70% classical oligodendrogliomas, help to distinguish from other types of gliomas. A/w better response to Rx & improved survival in both low-grade & anaplastic tumors. 1p/19q testing recommended in all pts w/oligodendrogliomas. (J Natl Canc Inst 1998;90:1473)
- Chromosome 10q loss: A/w poorer response to tx & shortened survival
- MGMT overexpression: A/w better response to tx
- IDH1 Mt: Good prognostic factor equally as strong as 1p/19q codeletion. IDH1 Mt are found in tumors w/& w/o1p/19q.

Workup and Evaluation

MRI brain & spine w/contrast:
- Low-grade tumors show ↑ signal on T2 images w/o enhancement. On CT, these tumors appear as low density masses w/o enhancement. Calcifications are suggestive but not specific for oligodendrogliomas.
- Anaplastic oligodendrogliomas: Typically characterized by contrast enhancement, but absence does not exclude anaplastic tumor.

Poor Prognostic Features: 3 or More of the Following

Age > 40 y

KPS < 70

Tumor > 6 cm

Tumor crossing midline

Preoperative neurologic deficit of more than minor degree

One or no deletion on 1p, 19q

Wild type IDH1 or 2

(JCO 2002;20:2076)

Initial Treatment for Oligodendrogliomas

Optimal management is controversial for low-grade oligodendrogliomas, w/c can be very indolent tumors.
Surgery: When possible, maximal safe resection is recommended. Surgical resection appears to confer survival benefit based on available retrospective data & may delay malignant progression & recurrence. No randomized data comparing surgery vs. conservative approach of delayed surgery after POD in low-grade tumors. Extent of resection should be documented w/a T2-weighted or FLAIR MRI scan w/in 72 h of surgery
Adjuvant Radiation: No consensus on timing of postoperative EBRT. RT is often reserved for tx of recurrent disease. EORTC 22845 trial randomized pts w/lowgrade gliomas to either 54-Gy postoperative radiation or no immediate Rx. 5-y DFS was better w/immediate post-op radiation (44 vs. 37%, p = 0.02); however OS was similar. Long-term follow-up showed no OS benefit, but seizures were better controlled in pts receiving immediate post-op RT (EORTC 22845, Int J Radiat Oncol Biol Phys 2002;52:316 & Lancet 2005;366:985)
- Radiation dose: No benefit for higher dose RT, standard is 45-54 Gy.
Adjuvant Chemotherapy: Temozolomide or Procarbazine, lomustine, & vincristine (PCV)
- RTOG 9802 suggested PCV + RT in low-grade glioma improves PFS & OS benefit in pts surviving beyond 2 y (JCO 2012;30:3065). Data is controversial, no way of selecting the pts who will survive beyond 2 y. Majority have not adopted as standard adjuvant chemotherapy.
- EORTC 26951 & RTOG 9402 showed chemotherapy + RT improves OS vs. RT alone (42 vs. 30 mos) in pts w/anaplastic oligodendroglioma w/codeletion 1p/19q (JCO 2012;30; JCO 2006;24:2707)