Bethesda Handbook of Clinical Oncology, 2nd Edition

Other Malignancies

33

Central Nervous System Tumors

Patrick J. Mansky*

1. Paul Duic^†

Howard A. Fine^‡

*National Center for Complementary and Alternative Medicine, National Institutes of Health Bethesda, Maryland

^†Department of Emergency Medicine, Johns Hopkins University Baltimore, Maryland

^‡Neuro-Oncology Branch, National Cancer Institute and National Institute of Neurologic Disorders, National Institutes of Health Bethesda, Maryland

Primary brain tumors represent a diverse spectrum of diseases that uniformly pose a unique problem to the practitioner because of their intracranial location. Brain tumors represent the second most common neurologic cause of death after stroke, but only the tenth most common cause of death from cancer. Nevertheless, they are a major cause of mortality from cancer in young adults and children. Most adult brain tumors occur in the cerebral hemispheres, but two thirds of all pediatric brain tumors are infratentorial.

During autopsy, metastatic brain tumors can be found in 25% to 40% of patients with systemic cancer. Early detection and accuracy of diagnosis have markedly improved because of advances in computerized tomography (CT) and magnetic resonance imaging (MRI). Despite the improvements, the prognosis for most forms of malignant brain tumors remains extremely poor. The mainstays of therapy remain surgery and radiation, whereas chemotherapy is beneficial only in a select group of tumors.

EPIDEMIOLOGY

According to the Surveillance, Epidemiology, and End Results (SEER) registry for 1973 through 1987, the range of incidence of brain tumors is 2 to 19 cases per 100,000 persons per year, depending on age at diagnosis.

• Peak age: 0 to 4 years, 3.1 per 100,000 persons
• Plateau: 65 to 79 years, 17.9 to 18.7 per 100,000 persons
• 17,000 to 20,000 new cases per year
• Primary brain tumors comprise 2% of newly diagnosed malignancies per year in the United States.

Distribution

The most common central nervous system (CNS) tumors are derived from glial precursors. The distribution of tumor frequency by age is demonstrated in Table 33.1.

TABLE 33.1. Distribution of Tumor Frequency by Age

Histology Age (yr) 0–9 10–19 20–29 30–39 40–49 50–59 60–74 GBM, glioblastoma multiforme. From DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 6th ed. Philadelphia: Lippincott-Raven, 2001, with permission. Astrocytoma 60% 59% 76% 81% 86% 87% 91% Low-grade 10% 7% 5% 5% 3% 2% 2% Anaplastic 47% 43% 51% 55% 48% 39% 40% GBM 1% 7% 14% 18% 33% 44% 51% Mixed glioma 3% 4% 5% 6% 6% 4% 2% Oligodendroglioma 1% 4% 5% 6% 6% 4% 2% Ependymoma 9% 3% 4% 2% 1% 1% 1% Medulloblastoma 21% 10% 6% 2% 1% 0% 0% Embryonal/teratoid 1% 1% 0% 0% 0% 0% 0% Meningioma 0% 0% 1% 2% 1% 2% 2%

Mortality

There are an estimated 13,000 deaths from primary brain tumors per year. CNS tumors are the most prevalent solid tumors in childhood. In children younger than 15 years, brain tumors

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are the most frequent cancer-related causes of death. In the age group 15 to 59 years, CNS tumors are the third leading cause of cancer-related deaths. However, 80% of all primary brain tumor–related deaths occur in patients older than 59 years.

CLINICAL DIAGNOSIS

Common Symptoms (By Decreasing Frequency):

• Headache
• Seizure
• Cognitive/personality changes
• Focal weakness
• Nausea/vomiting
• Speech abnormalities
• Altered consciousness

Common Signs (By Decreasing Frequency):

• Hemiparesis
• Cranial nerve palsies
• Papilledema
• Cognitive dysfunction
• Sensory deficits
• Hemianesthesia
• Hemianopia
• Dysphasia

DIFFERENTIAL DIAGNOSIS

Tumors of the cerebrum may be differentiated by location according to age at onset of symptoms (see Table 33.2 and Fig. 33.1).

FIG. 33.1. Topologic distribution and preferred sites of primary central nervous system tumors. (From Burger PC, Scheithauer BW, Vogel FS. Surgical pathology of the nervous system and its coverings, 3rd ed. New York: Churchill Livingstone, 1991, with permission.)

TABLE 33.2. Differential Diagnosis

Location Adult Child Supratentorial Metastatic disease Astrocytoma Glioblastoma Glioblastoma Astrocytoma Oligodendroglioma Meningioma Sarcoma Oligodendroglioma Neuroblastoma Mixed glioma Mixed glioma Infratentorial Metastatic disease Astrocytoma Astrocytoma Medulloblastoma Glioblastoma Ependymoma Ependymoma Brainstem glioma Brainstem glioma Sellar/parasellar Pituitary tumor Craniopharyngioma Meningioma Optic glioma Epidermoid Base of skull Neurinoma Meningioma Chordoma Carcinoma Dermoid/epidermoid

Acute Complications of Intracranial Tumors

Because the skull's rigid nature does not allow for processes associated with intracranial expansion, brain lesions routinely result in structural displacement and life-threatening consequences. Following the path of least resistance, tentorial or foramen magnum herniation may ensue. Neurologic findings are described in Tables 33.3 and 33.4.

TABLE 33.3. Neurologic Findings

Tentorial/temporal lobe herniation Pupillary dilation Ptosis Ipsilateral hemiplegia Contralateral hemiplegia Homonymous hemianopia Midbrain syndrome Coma with rising blood pressure/bradycardia

TABLE 33.4. Neurologic Findings

Cerebellar/foramen magnum herniation Head tilt Stiff neck Neck paresthesias Tonic tensor spasms of limbs and body Coma Respiratory arrest

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PRIMARY BRAIN TUMORS VERSUS BRAIN METASTASES

Primary BrainTumors

Gliomas

Four major types of gliomas have been recognized on the basis of their presumed normal glial cell of origin:

1. Astrocytoma
2. Oligodendrocytoma

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3. Oligoastrocytoma (mixed glioma)
4. Ependymoma

Grading

The pathologic classification of primary brain tumors has been a controversial and constantly changing area secondary to the lack of prognostic relevance for most classification systems. In addition, the considerable intraobserver variability between neuropathologists in assessing the specific histologic subtypes of a given tumor, secondary to the subjective criteria

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of each pathologic classification schema, has made the classification of brain tumors even more confusing. A pathologic grading system recently proposed by the World Health Organization (WHO) has been generally accepted by most neuropathologists and incorporates the following features for determining the grade (level of aggressiveness) of each histologic subtype of tumor:

• Cellular atypia
• Mitotic activity
• Degree of cellularity
• Vascular proliferation
• Degree of necrosis

A general classification of primary brain tumors can be found in the subsequent text:

Grade 1

• Pilocytic astrocytoma
• Giant cell astrocytoma
• Ganglioglioma
• Dysembryoplastic neuroepithelial tumors

Grade 2

• Well-differentiated low-grade astrocytomas
• Oligodendrogliomas
• Ependymomas

Grade 3

• Anaplastic astrocytomas (AAs)
• Anaplastic oligodendrogliomas
• Anaplastic ependymal tumors

Grade 4

• Glioblastoma multiforme (GBM)
• Embryonal tumors

Epidemiology

Gliomas comprise 45% of all intracranial tumors, with peak age in the seventh decade. Table 33.5 shows the prevalence of the pathologic subtypes of gliomas in relation to other more common primary brain tumors.

TABLE 33.5. Epidemiology

Type % Glioblastoma 55.0 Astrocytoma 20.5 Ependymoma 6.0 Medulloblastoma 6.0 Oligodendroglioma 5.0 Choroid plexus papilloma 2.0 Colloid cyst 2.0

Molecular Genetics of Gliomas

Genetic alterations form a continuum of progressive anaplasia in gliomas (see Table 33.6). Whereas secondary or progressive gliomas often harbor mutations of p53 and overexpression

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of the platelet-derived growth factor (PDGF) receptor, they seldom show amplification of epidermal growth factor receptor (EGFR). By contrast, primary or de novo GBM usually lack p53 mutations and contain an amplified EGFR. To date, none of the molecular parameters has demonstrated any significant association with patient survival in GBM.

TABLE 33.6. Molecular Genetics of Gliomas

Genetic alteration Anaplasia Glioma variant GBM, glioblastoma multiforme; EGFR, epidermal growth factor receptor. TP53 mutation Low-grade Low-grade astrocytoma PDGF overexpression Loss of chromosome 17p and 22q CDKN2/p16 deletion Anaplastic astrocytoma RB mutation CDK4 amplification Loss of chromosome 9p, 19q, 11p MDM2 amplification/overexpression High-grade GBM EGFR amplification rearrangements PTEN mutation Loss of chromosome 10

Glioblastoma Multiforme

• GBM is the most common adult primary brain tumor, accounting for 10% to 15% of intracranial tumors.
• The age of peak incidence is 45 to 55 years; overall incidence is two to three per 100,000 population; sex distribution, male-to-female ratio is 3:2.
• Median survival is 6 months.

Localization

• GBM occurs equally everywhere in the brain and is proportional to the volume of brain tissue in that particular anatomic location.
• It is more likely to be bihemispheric than other types of tumors are.

Development

Development of GBM is de novo (“primary”) or is a progression from a lower grade precursor lesion (“secondary”).

Genetics

• p53 mutations
• EGFR amplification
• Loss of heterozygosity (LOH) on chromosome 10; phosphatase and tensin homolog (PTEN) deletions
• LOH on chromosome 17p
• Significant aneuploidy

Imaging Characteristics on Magnetic Resonance Imaging

• Heterogeneous hypointense or isointense mass on CT scan or on Tesla 1 (T1, relaxation time 1) MRI.
• Heterogeneously contrast-enhancing mass

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• Hypervascular appearance
• Calcifications are rare

Differential Diagnosis

• Brain metastasis
• Cerebral abscess
• Demyelinating/inflammatory process (i.e., multiple sclerosis)
• Radiation necrosis
• Single photon emission computerized tomography (SPECT) and MR cerebral perfusion imaging may be used to distinguish radiation necrosis (hypovascular) from tumor recurrence (hypervascular)

MR spectroscopy is being increasingly used to help distinguish tumor from other processes that are visualized on MRI.

Gliosarcoma is a variant, with a mesenchymal component and a greater tendency for dural invasion.

GBMs are characteristically infiltrative within brain parenchyma but rarely show extracerebral metastasis.

Therapy

Current treatment recommendations for malignant gliomas (i.e., high-grade astrocytomas and GBM) include surgical resection, adjuvant radiotherapy, and, in select patients, the addition of chemotherapy. Secondary to the infiltrative growth characteristics of malignant gliomas, tumors recur even after gross total primary resection.

An analysis of several Radiation Therapy Oncology Group (RTOG) trials created the survival categories according to patient characteristics, as shown in Table 33.7.

TABLE 33.7. Survival Categories by Patient Characteristics

Patient characteristics Tumor Median survival (mo) KPS, Karnofsky performance status. Age <50 yr, normal mental status Anaplastic astrocytoma 40–60 Age >50 yr, KPS >70, symptoms >3 mo Age <50 yr, abnormal mental status Anaplastic astrocytoma 11–18 Age >50 yr, symptoms <3 mo Age >50 yr Glioblastoma 11–18 Age <50 yr, KPS >70 Age >50 yr, KPS <70 or abnormal mental status Glioblastoma 5–9

Radiation therapy has demonstrated a clear survival benefit in several randomized clinical trials, increasing the median survival from 20 to 36 weeks. Irradiation usually includes the contrast-enhanced tumor volume or peritumoral edema with a margin of 2 to 3 cm. A total dose of 60 Gy is delivered in 30 to 33 fractions. Palliative treatment courses provide radiation to 30 Gy in 10 fractions over 2 weeks.

The role of chemotherapy in the treatment of malignant gliomas was established by the Brain Tumor Study Group (BTSG) in several phase III trials, introducing nitrosoureas as effective agents. Carmustine (BCNU), at a dose of 80 mg per m² given daily for 3 days, repeated every 6 weeks, increased median survival from 38 to 51 weeks in patients with GBM. There is no real rationale for administering the BCNU over 3 days, and, more commonly, it is now given as a single intravenous (i.v.) infusion of 200 mg per m² every 6 weeks.

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Recent data from a randomized European Organization for Research and Treatment of Cancer (EORTC) trial have established a new standard of care for patients with newly diagnosed glioblastoma. In this trial, temozolomide was given at a dose of 75 mg/m²/day every day throughout the 6 weeks of standard external-beam radiotherapy (60 Gy in 30 fractions). Temozolomide was then administered postradiotherapy at a dosage of 200 mg/m²/day for 5 days every 28 days for six cycles. Patients who received this regimen had a statistically significant increase in prolongation of survival compared to patients who received radiotherapy alone (median survival increased by approximately 2.5 months; 2-year survival increased from 9% with radiation alone to 28% with combined treatment).

The role of multiagent chemotherapy versus single-agent therapy with BCNU remains controversial. The most commonly used regimen is PCV (see Table 33.8), which has demonstrated durable responses of more than 50% in anaplastic oligodendrogliomas. Anaplastic astrocytomas, mixed gliomas, and recurrent oligodendrogliomas also have shown favorable responses to this regimen. Temozolomide is also active in these glial tumors; however, currently, there is no basis for comparing the activity of PCV and temozolomide (although the PCV regimen tends to be associated with a higher incidence of side effects).

TABLE 33.8. PCV Regimen: Procarbazine, Lomustine (CCNU), Vincristine

From Levin VA, Silver P, Hannigan J, et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic astrocytoma: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 1990;18:321–324, with permission. Procarbazine, 60 mg/m2/d PO for 14 d, on cycle d 8–21 (d 8–21; total dose/cycle, 840 mg/m2) Lomustine (CCNU), 110 mg/m2 PO d 1 (d 1; total dose/cycle, 110 mg/m2) Vincristine, 1.4 mg/m2/dose i.v. on d 8 and 29 (d 8 and 29; total dose/cycle, 2.8 mg/m2) Cycle duration is 6 wk; may be extended to 8 wk for hematologic recovery

Given the overall poor prognosis for patients with high-grade gliomas, new treatment strategies are needed. Possibly the most promising of such strategies is the use of new inhibitors of signal transduction pathways such as inhibitors of the EGFR, platelet-derived growth factor receptor (PDGFR), ras, and mTOR pathways. Other treatment strategies currently under investigation include therapeutic gene transfer and antiangiogenic and immunotherapeutic approaches.

Astrocytoma

Astrocytomas comprise 25% to 30% of all hemispheric gliomas.

Low-grade Diffuse Astrocytoma

• Grade II
• Accounts for approximately 5% of primary brain tumors
• Mean age, 34 years
• Distribution: mostly cerebral hemispheres but also in the brainstem
• Imaging characteristics on MRI:
• Little edema/mass effect
• Difficulty in distinguishing the astrocytoma from nonmalignant infarct/cerebritis/demyelination
• Rare calcifications
• Large area of white/gray matter changes
• Differential diagnosis: infarct or cerebritis

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Median survival for patients after surgery of 19% to 32% at 5 years and 10% at 10 years is surpassed by that for the patients treated with surgery and postoperative irradiation, which is 36% to 55% after 5 years and 26% to 43% after 10 years.

Therapy

Historically, radiation therapy has been the standard treatment. The timing and dose of radiation therapy have been questioned. Recent studies of several hundred patients with low-grade gliomas from the EORTC have demonstrated no survival benefit for 60 Gy of radiation compared to 54 Gy. Thus, 54 Gy of radiation is currently considered standard. In another EORTC trial, patients with low-grade gliomas were randomized between immediate radiation at the time of diagnosis versus delayed radiation until radiographic and/or clinical progression. Although median time to tumor progression was longer for the immediate radiotherapy group, there was no difference in overall survival.

Recent data demonstrated that temozolomide can induce significant (albeit slow) preradiation tumor regressions in low-grade astrocytomas, although it does not appear that such responses are generally prolonged.

Low-grade supratentorial astrocytomas of children respond for prolonged periods to carboplatin and vincristine, although pilocytic tumors (see subsequent text) tend to be more responsive than diffuse astrocytomas.

Pilocytic astrocytomas are a special subset of low-grade astrocytomas and represent the most common childhood astrocytic tumor. This is virtually the only type of astrocytoma for which cure is possible with complete surgical resection.

Prolonged stabilization and tumor regression can be seen both with radiotherapy and chemotherapy, with the carboplatin and vincristine regimen being the most commonly used.

High-grade Diffuse Astrocytoma

• Grade III
• Accounts for approximately 5% of primary brain tumors; mean age, 41 years
• Macroscopically indistinguishable from low-grade astrocytomas
• Survival: 2 to 5 years

Therapy

Early trials established the role of postoperative radiation therapy at a dose of approximately 60 Gy, increasing median survival time from 14 to 36 weeks. The introduction of postoperative chemotherapy with nitrosourea-based regimens such as PCV significantly increased survival, particularly in anaplastic astrocytoma, with 50% of patients being alive at 157 weeks. Two large retrospective studies from the University of California, San Francisco (UCSF) and the RTOG, however, suggest that the outcomes are just as good for patients treated with postradiation single-agent nitrosourea [i.e., BCNU and lomustine (CCNU)] as for those treated with PCV. There are currently no prospective data on the use of temozolomide in the postradiation setting for anaplastic gliomas. Nevertheless, on the basis of the proven activity of nitrosoureas in the postradiation setting in anaplastic gliomas and the proven activity of temozolomide in recurrent anaplastic gliomas, it is reasonable to extrapolate that temozolomide will prove to be active in the postradiation setting for anaplastic gliomas.

Brainstem Gliomas

Brainstem gliomas occur predominantly in children as a group of diffuse astrocytomas of all grades.

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The clinical course is often malignant, regardless of grade, with a typical presentation of cranial nerve VI and VII palsies.

Management

• Surgery: Brainstem gliomas are rarely resectable unless there is a very large exophytic component. Even then, the intrinsic component is never completely resectable. Infiltrating pontine gliomas are one of the few (if not the only) brain tumors for which treatment based purely on radiographic criteria, and without a tissue diagnosis, is considered appropriate.
• Radiation therapy: A dose of 60 Gy of radiation is delivered in standard fractionation. Earlier data pointing to an advantage for hyperfractionation have not held up.
• Chemotherapy: Regimens including CCNU, PCV, 5-fluorouracil, and hydroxyurea have been tested without clear survival benefits.

Oligodendrogliomas and Oligoastrocytomas (Mixed Gliomas)

• Diffuse cerebral tumors; often appear with prominent areas of calcification on CT scan
• Accounts for 5% to 10% of all gliomas
• May have better prognosis than astrocytomas
• Chemosensitive, particularly anaplastic oligodendroglioma; most promising regimen includes PCV and temozolomide
• Like astrocytomas, low-grade gliomas may progress to higher grade gliomas

Treatment

• Low-grade oligodendrogliomas are best treated by surgical resection if most of the radiographically visible tumor can be safely removed.
• Radiation therapy has been the historic treatment of choice for low-grade progressive and anaplastic oligodendrogliomas. Increasingly so, chemotherapy with PCV or temozolomide is being used either in the postradiation adjuvant setting or as neoadjuvant therapy in order to delay the potential long-term neurotoxicity of radiation therapy; particularly in the settings of large diffuse tumors that would require large-field radiation.

EPENDYMOMA

Ependymomas comprise a spectrum of tumors ranging from aggressive childhood intraventricular tumors to low-grade adult spinal cord lesions. Typical locations are on the ventricular surface and the filum terminale.

Epidemiology

• Ependymomas account for 2% to 7.8% of all CNS neoplasms.
• 75% of ependymomas are of low grade.
• 50% occur before the age of 5 years.
• Intracranial tumors: 60% infratentorial, 40% supratentorial (with 50% intraventricular).
• Overall incidence of spinal seeding, approximately 7% to 15.7% for high-grade infratentorial lesions, is increased in patients with uncontrolled primary lesions.

Imaging

CT scanning and MRI are highly suggestive of the presence of ependymomas (i.e., calcified mass on the fourth ventricle) but are not diagnostic.

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Management

Surgery

Survival benefit is noted only for complete resections that are confirmed by neuroimaging.

Radiotherapy

• When complete surgical resection is achieved, no adjuvant therapy is recommended for low-grade ependymomas.
• Radiation therapy is usually warranted for low-grade ependymomas that show radiographic signs of tumor progression and for which complete surgical resection is no longer possible. Radiation is also warranted for anaplastic ependymomas.
• The entire posterior fossa is treated in case of infratentorial ependymomas, whereas local fields are treated in case of supratentorial ependymomas.
• Craniospinal irradiation is warranted for evidence of seeding by cerebrospinal fluid (CSF) cytologic or radiographic studies, or for anaplastic ependymoma.

Chemotherapy

Multiple chemotherapeutic regimens have been tested in recurrent and anaplastic ependymomas. Generally, response rates have been very low, with few responses being maintained.

The role of chemotherapy in this disease remains investigational.

Prognosis

• Low-grade tumors: 5-year survival, 60% to 80%
• Anaplastic ependymoma: 5-year survival, 10% to 47%
• With surgery alone: long-term survival, 17% to 27%
• Surgery plus radiation: long-term survival, 40% to 87%
• Age is dominant prognostic factor; infants do poorly.

CHOROID PLEXUS TUMORS

These tumors occur mostly in ventricles; in adults, the occurrence is predominantly in the fourth ventricle. The spectrum of tumors ranges from aggressive supratentorial childhood tumors to benign cerebellopontine angle tumors of adulthood. An association with Li–Fraumeni syndrome and von Hippel–Lindau syndrome has been described.

Diagnosis

• Signs of increased intracranial pressure (ICP)
• Focal findings of the fourth ventricle: ataxia and nystagmus
• Anaplastic histologic changes warrant CSF examination for increased risk of disseminated disease.

Management

Surgery

Complete resection is the goal of surgery.

Radiation Therapy/Chemotherapy

Given the rarity of these tumors, there are few prospective studies to evaluate any uniform approach. Radiation therapy, in conjunction with chemotherapy, has been used with some

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benefit for choroid plexus carcinoma and anaplastic tumors. Combinations of doxorubicin, cyclophosphamide, vincristine, and nitrosoureas have been used, as well as intraventricular methotrexate and cytarabine. Studies to evaluate these approaches have not been undertaken.

MEDULLOBLASTOMA

Medulloblastoma is a malignant, “small, blue, round cell tumor” of the CNS.

Epidemiology

• Medulloblastoma forms 25% of all pediatric tumors, and is found predominantly in the posterior fossa in children.
• It is uncommon in adults.
• 30% to 50% of medulloblastomas have isochromosome 17q.
• It is associated with Gorlin syndrome and Turcot syndrome.

Clinical Presentation

The most common presenting symptoms include signs of increased ICP, and cerebellar and bulbar signs. Five percent to 25% of patients have CSF dissemination at diagnosis, with less than 10% of patients exhibiting systemic metastasis, commonly to the bone; 40% of patients have brainstem infiltration.

Risk Stratification

• Average risk: With incidence of localized disease at diagnosis, total or near-total resection achieved
• High risk: Perceived with disseminated disease and/or partial resection

Imaging

Typically, contrast-enhancing posterior fossa midline lesion, most frequently arising from cerebellar vermis, is visualized on CT scan or MRI.

Staging

• A modified Chang staging system (see Table 33.9), where the presence of disseminated disease is the most important factor, is currently used. The other important prognostic factors are age (worse in children younger than 3 years) and extent of resection (controversial).
• Evaluation is performed according to size, local extension, and presence of metastasis.
• CSF and spinal axis should be evaluated for metastasis with lumbar puncture and contrast-enhanced MRI scan.

TABLE 33.9. Chang Staging System

Stage Description T1 Tumor <3 cm in diameter, limited to midline position in the vermis, the roof of the fourth ventricle, and less frequently to the cerebellar hemisphere T2 Tumor >3 cm, further invading one adjacent structure or partially filling the fourth ventricle T3a Tumor invading two adjacent structures or completely filling the fourth ventricle, with extension into aqueduct of Sylvius, foramen of Magendie, or foramen of Luschka, producing marked hydrocephalus T3b Tumor arising from the floor of the fourth ventricle or brainstem and filling the fourth ventricle T4 Tumor further spreading through the aqueduct of Sylvius to involve the third ventricle or midbrain, or extending to the upper spinal cord M0 No evidence of gross subarachnoid or hematogenous metastasis M1 Microscopic tumor cells found in cerebrospinal fluid M2 Gross nodule seedings demonstrated in cerebellar–cerebral subarachnoid space or in the third or lateral ventricles M3 Gross nodule seedings in the spinal subarachnoid space M4 Extraneuraxial metastasis

Management

• Surgery: goal is complete resection.
• Radiation therapy: involves postoperative 35-Gy radiation to whole brain, with 15- to 20-Gy boost to posterior fossa. Average-risk patients may be cured with radiation alone.
• In children with nondisseminated disease, there is emerging evidence that 23.4-Gy radiation to the craniospinal axis, supplemented by 31-Gy local irradiation, in conjunction with vincristine, 1.5 mg per m²for eight doses, followed by adjuvant CCNU, 75 mg/m² PO, and cisplatin, 75 mg per m² i.v. every 6 weeks, along with vincristine once every week for three consecutive weeks out of every cycle of 6 weeks duration, showed equivalent overall survival to that for

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the regimen that included 36-Gy craniospinal radiation, with less long-term cognitive sequelae. Progression-free survival at 5 years was 79%.

• The most commonly used chemotherapeutic regimen is adjuvant CCNU, 75 mg per m²PO; cisplatin, 75 mg per m² i.v. every 6 weeks; vincristine, 1.5 mg per m² weekly during radiation for eight doses, and then once weekly for 3 weeks during adjuvant chemotherapy cycles.
• Small nonrandomized trials with select patients suggest that a small (<20%) percentage of patients who relapse after primary treatment can be successfully re-treated and remain disease free for more than 5 years with high-dose chemotherapy and stem cell support.

Prognosis

Progression-free survival after chemotherapy and radiation are as follows:

• High-risk patients: 40% to 60%
• Average- risk patients: 65% to 91%.

MENINGIOMAS

Epidemiology

Meningiomas are common, composing up to 39% of primary CNS tumors (usually benign).

Genetics

• Monosomy 22, with frequent mutation of NF2gene on 22q
• Malignant meningiomas frequently show loss of 1p, 10, and 14q
• Predisposition: female sex, ionizing irradiation, NF2, and breast carcinoma

Clinical Presentation

• Most common areas of presentation are parasagittal region, cerebral convexity, and sphenoidal ridge.
• Signs and symptoms include seizures, hemiparesis, visual field loss, and other focal findings.

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Management

Surgery

• Treatment goal is complete resection.
• Recurrence rate after complete resection is 7% at 5 years and 20% at 10 years (higher for incompletely resected meningiomas).

Radiotherapy

• Adjuvant irradiation should be considered only for meningiomas that have been subtotally resected. Radiation probably reduces recurrence after subtotal resection.
• Malignant meningiomas: Irradiation probably increases survival and should be considered in the postoperative adjuvant setting even after complete surgical resection.
• Dosing: benign meningiomas, 54 Gy in 1.8- to 2.0-Gy fractions; malignant meningiomas, dose should be increased to 60 Gy.

Chemotherapy

• There are no known effective drugs for meningiomas.
• Despite harboring estrogen and/or progesterone receptors, meningiomas have generally not been responsive to hormonal therapy with agents such as tamoxifen. Although a small phase II trial suggested that the antiprogestin, RU-486, had antimeningioma activity, a subsequent large randomized trial by the Southwestern Oncology Group (SWOG) of RU-486 versus placebo for locally unresectable meningiomas showed no benefit for the drug compared to the placebo.

PRIMARY BRAIN LYMPHOMA

Intracerebral lymphoma most frequently presents as parenchymal lymphoma; however, other anatomic sites such as the eye, meninges, or ependymal nodules may be found.

Primary CNS lymphoma is a rare tumor, accounting for less than 2% of all primary brain tumors. Over the last few decades, there has been a dramatic increase in the prevalence of this tumor in immunocompetent patients, currently exceeding the incidence of non-Hodgkin lymphoma (NHL).

Risk Factors

• Acquired immunodeficiency syndrome (AIDS)
• Immunosuppression for organ transplantation
• Autoimmune disease
• Congenital immunodeficiencies such as Wiscott–Aldrich syndrome

Clinical Presentation

• The clinical presentation of primary brain lymphoma includes symptoms of intracranial mass, with headaches and signs of increased ICP.
• The frontal lobe is the most commonly involved site, often with multiple lesions; personality changes and decreased level of alertness are common.
• Multifocal disease; 42% leptomeningeal seeding at diagnosis

Clinical Diagnosis

A tissue diagnosis is of paramount importance.

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Staging studies should include

• MRI of brain with gadolinium
• lumbar puncture
• ophthalmologic evaluation
• complete physical examination and blood work (including liver function tests)
• chest radiograph
• abdominal CT scan (optional if no other signs of systemic disease).

Management

Approximately 40% to 70% of tumors are highly steroid sensitive; therefore, steroids should be withheld, if at all possible, until a tissue diagnosis has been established. A ring-enhancing lesion that “disappears” after starting steroids is strongly suggestive of a CNS lymphoma, although other infectious (i.e., toxoplasmosis) and inflammatory/demyelinating diseases (i.e., multiple sclerosis) must be considered.

Surgery

Surgery has no role in therapy, but is used for confirmation of diagnosis.

Radiotherapy

Radiotherapy yields 80% to 90% radiographic complete response (CR), and is commonly dosed at 40 to 60 Gy to the entire brain and meninges (“C2” radiation); median survival is 12 to 18 months.

Chemotherapy

• Recent studies suggest that preradiation chemotherapy with high-dose methotrexate significantly increases median survival and the number of long-term survivors.
• Role of radiotherapy for patients who have CR to chemotherapy remains unknown.
• The likelihood of long-term treatment-induced neurocognitive toxicity is probably enhanced considerably in patients who receive combined-modality treatment.
• The two most widely utilized regimens for treating primary CNS lymphoma are the NABTT (New Approaches to Brain Tumor Therapy) high-dose methotrexate regimen and the MSKCC (Memorial Sloan-Kettering Cancer Center) regimen, both of which are detailed in Table 33.10.

TABLE 33.10. Chemotherapy

HD MTX, high-dose methotrexate; XRT, radiation therapy. From DeAngelis LM, Seiferheld W, Schold Sc et al. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10. J Clin Oncol 2002;20(24):4643–4648. NABTT Regimen: HD MTX 8 g/m2 q2wk, with leucovorin rescue to maximal response; Delay XRT until tumor progression; 22 patients treated; Overall response rate 74%; Median progression-free survival 12.8 mo; Median overall survival 22.8+ mo; No reported cases of delayed severe neurologic toxicity MSKCC Regimen: Five cycles of methotrexate 2.5 g/m2, vincristine 1.4 mg/m2 with maximum dose at 2.8 mg (2m2), procarbazine 100 mg/m2/day for 7 days (cycle 1,3,5), and intra-ventricular methotrexate 12 mg followed by whole-brain XRT to 45 Gy; 102 patients; 94% response to preradiation chemotherapy; Median progression-free survival 24.0 mo; Overall survival 3.9 mo; 15% of patients experienced severe delayed neurologic toxicity (1)

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GERM CELL TUMORS

Epidemiology

CNS germ cell tumors (GCTs) are typically located in the pineal region. The most common histologic type is germinoma, comprising 30% to 50% of all pineal tumors. Overall, however, this group of tumors represents a rare subgroup of less than 1% of all intracranial tumors.

Diagnosis

Because the pineal region involves an area close to the center of the brain, symptoms are generally related to increased ICP and ocular pathway cranial nerve palsies.

• Obstructive hydrocephalus: headache, nausea, vomiting, and lethargy
• Cranial nerve palsies: diplopia and upward-gaze paralysis
• Elevations in serum tumor marker levels: α-fetoprotein (AFP), β-human chorionic gonadotropin (β-HCG), and placental alkaline phosphatase (PLAP)

Management

Surgery

• Microsurgical infratentorial supracerebellar or supratentorial approach under the occipital lobe is used to establish diagnosis and to attempt resection in radioresistant tumors.

Radiation Therapy

Germinomas are exquisitely radiosensitive.

• Localized germinomas are treated with 24-Gy radiation to the ventricular system, and with 26 Gy to tumor.
• Disseminated germinomas are treated with 20- to 35-Gy radiation to craniospinal axis in addition to systemic chemotherapy.
• Nongerminomatous GCTs are irradiated after chemotherapy. Localized tumors: 24 Gy to ventricular system, 54- to 60-Gy boost to tumor. Disseminated tumors: craniospinal irradiation with 54 to 60 Gy to tumor, 45 Gy to ventricles, and 35 Gy to spinal cord.

Chemotherapy

• Chemotherapy is used primarily for nonseminomatous GCTs; the overall contribution of chemotherapy remains unclear.
• Commonly used regimens include cisplatin/etoposide/bleomycin (PEB), carboplatin/etoposide/vinblastine in doses used for extragonadal GCTs.
• Teratoma: treatment is primarily surgical, possibly with radiation.

Prognosis

Germinomas: 5-year survival is greater than 80% with radiation only. The prognosis is significantly poorer for nonseminomatous, mixed GCTs.

• High survival is seen in mature teratomas.

BRAIN METASTASES

Epidemiology

Brain metastases represent the most prevalent intracranial malignancy. With an estimated incidence of 80,000 to 170,000 cases per year in the United States, compared to 17,000 to

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20,000 newly diagnosed primary brain tumors, the importance of diagnosis and management of this disease is well understood (see Table 33.11 and 33.12).

TABLE 33.11. Frequency of Brain Metastases

Primary tumor Frequency (%) Lung cancer 50 Breast cancer 15–20 Unknown primary 15–19 Melanoma 10 Colon cancer 5

TABLE 33.12. Distribution By Location

Location Frequency (%) Hemispheres 80 Cerebellum 15 Brainstem 5

Ten percent to 30% of adults and 6% to 10% of children with cancer develop symptomatic brain metastases, with lung and breast cancers being the most common primary cancers in adults. Sarcomas, neuroblastomas, and GCTs appear to be most common in pediatric metastatic brain disease (Tables 33.13 to 33.14).

TABLE 33.13. Diagnosis: Clinical Signs

Sign Frequency (%) Hemiparesis 44 Mental status changes 35 Gait ataxia 13 Hemisensory loss 9 Papilledema 9

TABLE 33.14. Diagnosis: clinical symptoms

Symptom Frequency (%) Headache 42 Mental changes 31 Focal deficit 27 Seizure 20 Gait ataxia 17 Speech disturbance 10 Sensory problems 6

Differential Diagnosis

• Primary brain tumors
• Abscess
• Demyelination
• Cerebral infarction

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• Cerebral hemorrhage
• Progressive multifocal leukoencephalopathy
• Radiation necrosis

The false-positive rate for single brain metastasis may be as high as 30%. Nonmetastatic brain lesions are equally divided between primary brain tumors and infections. Meningioma must be considered in patients with primary breast cancer with a dural-based brain lesion because the prevalence of this primary brain tumor increases in breast cancer.

Imaging

Contrast-enhanced MRI is the diagnostic imaging modality of choice. Features of MRI that favor the diagnosis of brain metastasis include

• multiple lesions
• location at gray–white matter junction
• high ratio of vasogenic edema to tumor size.

If imaging modalities and clinical history do not provide sufficient information to render a diagnosis, a biopsy of the lesion is indicated.

Brain Metastasis with Unknown Primary

A chest radiograph should be obtained in any patient with a new brain mass because 60% of patients with brain metastasis of unknown primary have a lung mass from a pulmonary malignancy or pulmonary metastasis of a primary in a different location. A CT scan of the chest considerably increases the likelihood of finding a lung mass if the chest radiograph is nondiagnostic.

To determine the extent of metastatic disease, CT scans of the abdomen and pelvis and a bone scan should be performed.

Management

Symptomatic Therapy

Reduction of symptomatic edema: Dexamethasone, 10 mg loading dose, followed by 4 mg four times a day.

• Symptomatic improvement should be expected within 24 to 72 hours.
• Imaging studies may not show a decrease of cerebral edema for up to 1 week.
• Steroid should be tapered after completion of irradiation or earlier if cerebral edema is minimal.

Seizure Management

Because infratentorial metastases carry a very low risk for seizures, anticonvulsant therapy is usually not indicated. The role of prophylactic anticonvulsant therapy remains controversial in patients with supratentorial brain metastasis without prior seizures who have not had surgery. Generally after seizure activity has occurred or after a patient has undergone craniotomy, phenytoin therapy is initiated. Close monitoring is advised because dexamethasone and phenytoin mutually increase the clearance of phenytoin, and the number of reports suggesting a correlation between Stevens–Johnson syndrome and palliative whole-brain irradiation in patients taking phenytoin is increasing. Secondary to the fact that phenytoin (like most other older antiepileptic drugs) induces hepatic cytochrome P450 isoenzymes, thereby considerably

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altering the metabolism and pharmacology of many other drugs such as chemotherapeutic agents, some physicians are moving toward initiating seizure prophylaxis with newer agents that do not induce hepatic enzymes, such as Keppra, despite the fact that most of these agents (including Keppra) are not approved by the U.S. Food and Drug Administration (FDA) for monotherapy.

Surgery

Factors influencing the decision favoring surgical resection include

• extent of systemic disease
• neurologic status of patient
• number of cerebral metastases
• interval between diagnosis of primary cancer and occurrence of brain metastasis
• primary cancer
• location of tumor.

Single brain metastasis: Several controlled studies suggest a benefit of surgery combined with whole-brain irradiation for patients with single brain metastasis and stable extracranial disease.

Multiple brain metastases: For patients with multiple brain metastases, the role of surgery is generally limited to

• large, symptomatic, or life-threatening lesions
• tissue diagnosis in unknown primary
• differentiation of metastasis from primary brain tumor like meningioma.

The value of resection of multiple brain metastases with therapeutic intent has not been established.

Radiation Therapy

• Radiation therapy is considered the primary therapy for patients with brain metastasis.
• Whole-brain irradiation increases median survival to 3 to 6 months.
• Overall response rate is 64% to 85%.
• Cranial nerve deficit improvement is seen in 40% of patients.

Fractionation Schedule

• From 30 to 50 Gy in 1.5- to 4-Gy fractions
• Most common schedule: 30 Gy in 10 fractions over 2 weeks
• Patients with good prognosis: more prolonged fractionation such as 40 Gy in 2-Gy fractions may reduce long-term morbidity.

Postoperative Radiation Therapy

• A 62% reduction in treatment failure is observed with postoperative radiation therapy.
• There is a 30% reduction in risk of death from neurologic causes.
• There is no improvement of overall survival or duration of functional independence.
• Dosing: 50.4 Gy in 28 fractions.

Late Toxicities

• Dementia occurs in 11% of patients receiving a total dose of radiation >30 Gy
• Recommended dosing: 40 to 45 Gy in 1- to 2-Gy fractions.

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Reirradiation

• Radiosurgery is recommended for patients with solitary or fewer than three metastases.
• Whole or partial brain irradiation is for patients who are not eligible for radiosurgery/chemotherapy.
• Clinical response is from 42% to 75%.
• Median survival is from 3.5 to 5 months.
• Dosing schedules vary without established consensus.

Radiosurgery

Indications

• Young patient
• Good performance status
• Limited extracranial disease
• One to two small lesions
• Recurrent brain metastasis after whole-brain irradiation.

Adverse Prognostic Factors

• Poor performance status
• Progressive systemic disease
• Infratentorial location
• Large tumor size
• Multiple lesions.

Interstitial Brachytherapy

• There is, at present, no real indication for interstitial brachytherapy.

Chemotherapy

In select malignancies, brain metastases may show responses to systemic treatment of the underlying cancer.

Breast Cancer

Regimens including cyclophosphamide/5-fluorouracil/cisplatin (CFP), cyclophosphamide/methotrexate/5-fluorouracil (CMF), and doxorubicin (Adriamycin)/cyclophosphamide (AC) have been used, and are generally directed at the systemic cancer. Responses are noted in 50% to 70% of cases. There appears to be a survival advantage in patients who respond.

Small Cell Lung Cancer

Regimens including etoposide and platinating agents have been used. Overall response rates for primary brain metastasis approach 76%. Response rates decrease to 43% on CNS relapse.

Prognostic Factors

• Karnofsky Performance Status more than 70
• Age less than 65 years
• Controlled primary disease
• No extracranial metastasis

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• Median survival ranges from 2.3 to 7.1 months depending on the presence of good prognostic indicators (Table 33.15).

TABLE 33.15. Prognosis (Median Survival in Months)

Untreated brain metastasis 1 mo Addition of steroids 2 mo With whole-brain irradiation surgery and whole-brain radiation 3–6 mo Single metastasis, limited extracranial disease, 10–16 mo

REFERENCES

1. DeAngelis LM, Seiferheld W, Schold SC, et al. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10. J Clin Oncol 2002;20:4643–4648.

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