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Neurooncology
Tumors of the central nervous system (CNS) are a significant cause of morbidity and mortality. In the United States, it is estimated that 22,000 new cases and 13,000 deaths caused by primary malignant CNS malignancies occur annually. Additionally, 28,000 new cases of meningiomas, which are more than 90% benign tumors, are diagnosed each year. Metastatic CNS tumors significantly outnumber primary tumors; an estimated 170,000 cases of brain metastases are diagnosed in the United States yearly. Fig. 23.1 lists the most common primary CNS neoplasms in adults by location.
Radiographic differential diagnosis of solitary CNS neoplasms in the adult patient, by location. PNET, primitive neuroectodermal tumor.
Symptomatic Management in Neurooncology
Corticosteroids
The primary indication of corticosteroids in CNS tumors is to control brain and spinal cord vasogenic edema. Corticosteroids have significant side effects such as insomnia, hyperglycemia, myopathy, psychiatric effects, and opportunistic infections, and some studies suggest that they may decrease overall survival in glioma patients. Patients with asymptomatic CNS tumors and those with symptoms unrelated to vasogenic edema do not benefit from or require corticosteroids. In suspected cases of primary CNS lymphoma (PCNSL), corticosteroids should be avoided whenever possible because they decrease the diagnostic yield of biopsies. Dexamethasone is the standard corticosteroid in CNS tumors because of its virtual lack of mineralocorticoid effect and lower serum protein binding, which leads to higher CNS levels. There are no specific dexamethasone dosing guidelines; patients should receive the smallest amount needed to control the neurologic symptoms caused by vasogenic edema. A standard starting dose for brain vasogenic edema is dexamethasone 4 mg twice daily . Patients should not be reflexively started on proton pump inhibitors when started on corticosteroids, and this should be reserved for patients with a history of gastritis or gastric or duodenal ulcers. If corticosteroids are used in a high dose (≥ 20 mg of prednisone or approximately 3.2 mg of dexamethasone daily) chronically (≥ 4 weeks), prophylaxis for Pneumocystis jiroveci must be started.
Antiepileptic Drugs
Although seizures are frequent in both primary and metastatic brain tumors, prophylactic antiepileptic drugs are not indicated in patients with CNS tumors who have never had a seizure. Primary seizure prophylaxis is only recommended in the immediate postoperative period after a brain tumor resection. Prophylactic antiepileptic drugs in patients undergoing brain tumor resection can reduce the risk of seizures by 40% to 50% in the first postoperative week, but they do not prevent seizure incidence afterward and should be quickly tapered off. On the other hand, antiepileptic drugs should be started in any patient who has experienced a seizure at tumor presentation or during the CNS tumor disease course, including after a single seizure episode. In general, nonenzyme-inducing antiepileptic drugs are preferred to avoid interactions with chemotherapies or targeted therapies.
Anticoagulants
Patients with CNS malignancies have an increased incidence of venous thromboembolic events. CNS tumor without acute hemorrhage is not a contraindication for prophylactic doses of unfractionated or low-molecular-weight heparin during hospitalization. Up to 30% of patients with high-grade gliomas develop symptomatic deep venous thrombosis or pulmonary embolism. CNS malignancy is not an absolute contraindication for full-dose anticoagulation when active or acute intracranial hemorrhage has been excluded. In fact, chronic anticoagulation is preferred over inferior vena cava (IVC) filters, which have frequent complications such as recurrent embolic events, IVC or filter thrombosis, severe postphlebitic syndrome, and chronic leg swelling.
Gliomas
The histopathologic criteria for the diagnosis of gliomas are based on the World Health Organization (WHO) classification. Grade I gliomas (pilocytic astrocytoma) are rare in adults and the only potentially curable glioma with a gross total resection. Grade II (low-grade) and grade III (anaplastic) gliomas can be subdivided into astrocytomas and oligodendrogliomas based on the morphology and molecular features; oligodendrogliomas must have both isocitrate dehydrogenase (IDH) mutation and 1p/19q chromosome codeletion. Glioblastomas (grade IV gliomas) are the most common and most aggressive primary brain tumors in adults; they are characterized by the presence of microvascular proliferation, necrosis, or both on pathology.
Epidemiology
Gliomas are the most common primary brain tumor in adults, with approximately 18,000 people diagnosed in the United States each year. Their incidence is slightly higher in men than women, and in Caucasians compared with African Americans. Glioblastomas account for more than 50% of cases of gliomas; incidence increases with age and peaks in the seventh decade of life. Anaplastic glioma peak of incidence is in the fifth decade of life, whereas low-grade gliomas are more common in patients between ages 30 and 40.
Diagnosis
Low-grade gliomas are nonenhancing infiltrative tumors with minimal or no vasogenic edema ( Fig. 23.2 ). Oligodendrogliomas can have calcification or hemosiderin deposits from prior bleeding. Anaplastic gliomas have variable degrees of vasogenic edema, and about 50% show some signs of contrast enhancement on magnetic resonance imaging (MRI) scans. Glioblastomas have irregular borders, almost always enhance, and often have central necrosis and vasogenic edema ( Fig. 23.3 ). Biopsy (or, whenever feasible, surgical resection) is required for histologic diagnosis because imaging features have limited predictive value. Histologically, low-grade gliomas show mild nuclear atypia and increased cellularity, whereas anaplastic gliomas are characterized by the presence of mitoses, and glioblastomas have microvascular proliferation and tumor necrosis.
Treatment
Newly Diagnosed Gliomas
Surgery
Maximal safe resection is recommended for all glioma grades and subtypes whenever the tumor is surgically accessible and there are no absolute medical contraindications to surgery. A complete macroscopic resection, however, is almost never curative because grade II–IV gliomas infiltrate the normal brain. Nevertheless, surgical resection provides tissue for accurate diagnosis and molecular studies, can improve neurologic symptoms, decreases dependence on corticosteroids, and improves quality of life. Moreover, retrospective and prospective nonrandomized studies suggested that more extensive tumor resection is associated with longer survival in both low-grade and high-grade (grade III and IV) gliomas.
Because of tumor location, not all gliomas are amenable to resection, but, if feasible, a biopsy should be performed to provide histologic diagnosis. Neurosurgical advances such as neuronavigation, intraoperative brain mapping techniques, awake craniotomies, and intraoperative MRI allow neurosurgeons in specialized centers to resect CNS tumors previously considered unresectable successfully. Certain tumors located in the brain stem may have a high risk of biopsy complications, and the diagnosis and treatment decision may be based on neuroimaging and clinical features only.
Radiotherapy
Radiotherapy increases median survival in patients with glioblastomas from approximately 4 months with supportive care only to about 12 months. The most used protocol for anaplastic gliomas and glioblastomas delivers 200-cGy fractions of focal radiation over a 6-week period to a total dose of 6000 cGy. For low-grade gliomas, lower total doses (a total of 4500 to 5400 cGy fractionated over 5–6 weeks) are more commonly used. The best timing for radiotherapy in low-grade gliomas, however, remains controversial. For patients with low-grade gliomas who had an optimal resection, tumors < 6 cm, no neurologic symptoms other than seizures, and age < 40 years, the recommendation is close surveillance with brain MRI scans, because upfront radiation or chemotherapy likely does not improve survival.
Chemotherapy
The most commonly used chemotherapy in gliomas is the alkylating agent temozolomide . Temozolomide is considered standard of care in the initial treatment of both anaplastic astrocytomas and glioblastomas. For low-grade gliomas and oligodendrogliomas, the role of temozolomide is less established. For newly diagnosed glioblastoma and anaplastic astrocytomas, radiotherapy and temozolomide ( 75 mg/m 2 daily during radiotherapy followed by 6–12 cycles at 150–200 mg/m 2 on days 1–5 of 28-day cycles ) are recommended.
The tumor DNA damage caused by temozolomide and other alkylating agents can be reversed by a DNA repair enzyme encoded by the O -6-methylguanine-DNA methyltransferase ( MGMT ) gene. Glioblastomas with methylation of the MGMT promoter, and consequently less transcription of MGMT gene and lower levels of this DNA repair enzyme, have better outcomes on temozolomide than those with the unmethylated MGMT promoter. For glioblastomas with unmethylated MGMT promoter, withholding temozolomide is acceptable because of the low likelihood of benefiting from alkylating chemotherapy.
Oligodendrogliomas are more sensitive to chemotherapy compared with other gliomas. The best timing for chemotherapy for oligodendrogliomas, however, is not defined. It is unclear if chemotherapy can safely replace radiotherapy as the initial treatment of newly diagnosed anaplastic oligodendrogliomas. An old chemotherapy regimen called procarbazine , CCNU (also called lomustine), and vincristine (PCV) in addition to radiotherapy improves outcomes in oligodendrogliomas compared with radiotherapy alone; nevertheless, PCV has significant toxicity, and its use has been declining over the years.
Wafers containing the alkylating agent carmustine (Gliadel) implanted in the surgical cavity at the time of tumor resection are approved by the Food and Drug Administration (FDA) for recurrent or newly diagnosed high-grade (grade III or IV) gliomas but are rarely used. Gliadel’s clinical benefit is quite limited, and it has unique side effects (surgical infection, cerebrospinal fluid [CSF] leak); moreover, Gliadel has not been directly compared with systemic chemotherapy in a clinical trial.
Tumor-Treating Fields
Tumor-treating fields (TTFields) are a noninvasive therapeutic modality that delivers low-intensity alternating electric fields through arrays over the scalp. TTFields have antimitotic activity, and they have been approved for treatment of glioblastoma; TTFields usually start about 4 weeks after the completion of radiation and temozolomide. The recommendation is to use TTFields for about 18 hours daily in conjunction with adjuvant temozolomide. TTFields can be used up to 2 years, and they improve overall survival in this population.
Recurrent Gliomas
There is no accepted standard of care for recurrent gliomas. A subset of patients may benefit from another surgical resection at the time of recurrence. Patients with low-grade gliomas who did not undergo radiotherapy at the time of diagnosis should receive radiation at the time of recurrence or progression. Reirradiation for recurrent high-grade gliomas may be an option for patients with a long interval from the initial radiotherapy and smaller tumors. Bevacizumab , a monoclonal antibody with antiangiogenic activity by blocking vascular endothelial growth factor (VEGF), is approved by the FDA for recurrent glioblastoma. Bevacizumab, however, does not improve survival in recurrent or newly diagnosed glioblastomas. Despite having no long-term benefit for glioma patients, bevacizumab is still used because it has potent antivasogenic edema control and can help symptom control. The approved regimen for glioblastomas is 10 mg/kg intravenously (IV) every 2 weeks .
Other chemotherapy options for recurrent gliomas include nitrosoureas (lomustine and carmustine) and carboplatin. TTFields are also approved for recurrent glioblastomas. Enrollment in a clinical trial including immunotherapies, oncolytic viruses, and new treatment modalities should be encouraged because standard options have insufficient efficacy.
Prognosis
Tumor grade is a significant prognostic factor, because the median survival of patients with glioblastoma (grade IV glioma) is only 15 to 18 months, whereas the survival rate of patients with anaplastic gliomas varies between 2 and 5 years. The survival of patients with low-grade gliomas ranges from 3 to 10 years. Oligodendroglial tumors have a better prognosis than their astrocytic counterparts of the same grade. Nevertheless, patients with identical tumor histology and grade can have markedly different clinical courses and survival, likely reflecting the significant molecular heterogeneity of these tumors. Clinical factors associated with better outcomes, other than histology and tumor grade, include younger age at diagnosis, better performance status, and more extensive resection.
Primary Central Nervous System Lymphoma
PCNSL is an extranodal non-Hodgkin lymphoma involving the brain, eyes, meninges, or spinal cord in the absence of systemic lymphoma. Histologically, the vast majority of cases are diffuse large B-cell lymphomas.
Epidemiology
PCNSL is relatively uncommon, with approximately 1300 new cases diagnosed in the United States each year. Immunosuppression caused by HIV or iatrogenic causes (i.e., medications to prevent solid organ transplant rejection) markedly increases the risk of PCNSL. The incidence of PCNSL in HIV patients has declined significantly since the introduction of highly active antiretroviral therapy. PCNSL associated with immunosuppression is an Epstein-Barr virus (EBV)–mediated malignancy. EBV has tropism for B lymphocytes; immortalizes B lymphocytes; and, under immunosuppressive conditions, its infection may result in transformation to B-cell lymphoma.
Diagnosis
In immunocompetent patients with PCNSL, the brain MRI usually shows a diffusely enhancing tumor in the deep white matter or basal ganglia with surrounding vasogenic edema. The most typical characteristics of PCNSL on MRI scans are diffuse enhancement on T1 post gadolinium with absence of necrosis, hypointense tumor on T2-weighted imaging, and tumor restriction on diffusion-weighted imaging ( Fig. 23.4 ). In immunosuppressed patients, tumors may have central necrosis. The diagnostic procedure of choice is a stereotactic brain biopsy. In rare circumstances, diagnosis can be made through vitreal biopsy or CSF cytology, but these tests have low diagnostic yield and should only be considered if there is no brain parenchymal lesion amenable to biopsy. In immunosuppressed patients, EBV polymerase chain reaction (PCR) in the CSF in conjunction with increased uptake on positron emission tomography (PET) or singe-photon emission computed tomography (SPECT) may suggest lymphoma, but diagnostic confirmation with a brain biopsy is preferable.
An ophthalmologic exam with slit-lamp to exclude ocular lymphoma should be performed in all patients. Patients with spinal symptoms should undergo a total spine MRI scan with gadolinium. Patients with presumed PCNSL must undergo HIV serology and a body computed tomography (CT) or PET to exclude systemic involvement. Testicular ultrasound in older men and bone marrow biopsy may be useful in selected cases.
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