April Fitzsimmons Eichler and Tracy T. Batchelor
I. PRIMARY BRAIN TUMORS
According to the Central Brain Tumor Registry of the United States (CBTRUS), there were an estimated 51,510 cases of new malignant and nonmalignant primary brain tumors (PBTs) diagnosed in the United States in 2007. This includes an estimated 20,500 new cases of malignant brain and central nervous system (CNS) tumors, representing 1.42% of all malignant cancers and accounting for 12,740 deaths in the same year. The age-adjusted 5-year relative survival from 1999 to 2005 for all malignant PBT—including lymphomas, leukemias, tumors of the pituitary and pineal glands, and olfactory tumors of the nasal cavity—was 35%. The only established risk factor for PBT is ionizing radiation at high doses, which has been associated with an increased incidence of nerve sheath tumors, meningiomas, and gliomas. However, radiation-associated tumors account for only a small percentage of PBTs.
Gliomas account for 36% of all PBTs and include astrocytic, oligodendroglial, and ependymal tumors. Astrocytomas are the most frequent type and these tumors manifest a wide spectrum of clinical behavior. Malignant gliomas—including anaplastic oligodendroghoma, anaplastic astrocytoma, and glioblastoma (GBM the most common malignant PBT)—are not curable, although each may respond to radiation and chemotherapy. Astrocytomas are graded based on the presence or absence of the following histologic features: nuclear atypia, mitoses, endothelial proliferation, and necrosis.
1. Grades I and II astrocytoma. Pilocytic astrocytomas are World Health Organization (WHO) grade I tumors that most commonly arise in the posterior fossa. These tumors are most common in the pediatric population and can be cured if a total resection is achieved. WHO grade II astrocytomas (low-grade astrocytomas) are most commonly observed in the third and fourth decades of life. This tumor typically appears as a nonenhancing, diffuse, hypointense mass on T1-weighted magnetic resonance imaging (MRI). Even with a characteristic appearance, biopsy is necessary to determine the histologic subtype and because up to 30% of nonenhancing tumors are shown to be anaplastic (WHO grade III) at the time of surgery. Median survival for low-grade gliomas (LGGs)—which includes low-grade astrocytoma, oligoastrocytoma, and low-grade oligodendroglioma—ranges from 7 to 9 years with a 5-year survival of 60% to 70%. Important prognostic factors for survival include age, performance status, preoperative tumor size, extent of resection, and histology, with astrocytic tumors fairing worse than oligodendroglial tumors.
If feasible, a maximal safe resection should be performed and then the patient should be followed regularly with serial MRI studies and clinical examinations. Data from four prospective randomized clinical trials in adults with LGG indicate that (1) postoperative radiation therapy compared with observation is associated with improved progression-free survival but not overall survival and (2) radiation doses of 45 to 54 Gy result in similar outcomes to higher doses (59 to 65 Gy) and are associated with improved tolerability. Based on these data, postoperative radiation therapy is often recommended for patients after a subtotal resection or biopsy, particularly if there are additional “high risk” features such as advanced age (>40 years), elevated MIB-1 labeling index (>3% to 5%), or pure astrocytoma histology. Even in low-risk LGG patients, defined in one recent prospective observation study as adults 40 years of age with neurosurgeon-determined gross-total resection, the risk of tumor progression at 5 years may be as high as 50%.
In the event of tumor progression on computed tomography (CT) or MRI, further surgery, if possible, may be performed and involved field radiation (IFR) or chemotherapy is recommended, depending on the histologic subtype. If, at the time of the recurrence, the histopathology demonstrates a higher grade astrocytoma, chemotherapy can be initiated, which will be discussed in the following section.
2. Grades III and IV astrocytoma. Anaplastic astrocytoma (WHO grade III) occurs most commonly in the fourth and fifth decades, whereas glioblastoma (WHO grade IV) occurs most commonly in the fifth and sixth decades. Median survival times are 24 to 36 months and 12 to 15 months, respectively. These two types of tumors may be indistinguishable by MRI because both often appear as diffuse hypointense lesions on T1-weighted images and both readily enhance after administration of intravenous contrast. These tumors are most commonly observed in the cerebral hemispheres and can have cystic or hemorrhagic components.
Histologic diagnosis is made by stereotactic biopsy or resection. Surgical debulking is the preferred initial treatment to minimize neurologic morbidity. Retrospective studies and the adjusted analysis of a prospective randomized trial of fluorescence-guided resection have suggested that gross total resection is associated with longer survival. Resection also relieves mass effect, which allows a patient to better tolerate subsequent IFR and often allows discontinuation of corticosteroids. Following surgery, standard therapy includes IFR up to 60 Gy, given in combination with temozolomide for grade IV tumors (see later). Management of anaplastic astrocytoma remains controversial because of a lack of randomized prospective data, but postoperative IFR or IFR with concurrent temozolomide are the most common treatment approaches. Positive prognostic factors include high Karnofsky performance score, gross total resection, and younger age. In addition, multiple studies have now shown that methylation of the O6-methylgua-nine-DNA methyltransferase (MGMT) promoter is prognostic of improved survival and may be predictive of increased responsiveness to temozolomide chemotherapy in GBM.
a. Chemotherapy. Chemotherapy is now considered the standard of care for newly diagnosed glioblastoma based on the results of a European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) randomized, multicenter trial of 573 patients comparing IFR (radiation arm) with IFR plus concurrent temozolomide (TMZ) followed by 6 months of postradiation, monthly TMZ (chemoradiation arm). Patients treated with chemoradiation had a median survival of 14.6 months, compared with 12.1 months in the radiation arm. In addition, the 2- and 5-year survival rates were 27% and 10% in the chemoradiation group compared with 11% and 2% in the radiation group, respectively.
In 2009, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), as a single agent for use in treatment of recurrent glioblastoma. Approval was based on two prospective studies showing a 20% to 30% objective response rate and a median response duration of approximately 4 months. In addition, bevacizumab was associated with decreased steroid use over time. The most frequent adverse events were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3 or higher adverse events were similar to those seen in other primary cancer types and included bleeding/hemorrhage, CNS hemorrhage, hypertension, venous and arterial thrombosis, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. There is also a large experience with bevacizumab in combination with irinotecan (CPT-11) for recurrent malignant glioma. However, in a randomized noncomparative trial, median progression-free survival and overall survival were not significantly different in the combination arm (5.6 months and 8.7 months, respectively) compared with the bevacizumab monotherapy arm (4.2 months and 9.2 months) and toxicity was higher with combination therapy. Several large randomized placebo controlled trials are investigating the efficacy of bevacizumab in combination with chemoradiation for newly diagnosed glioblastoma.
Recurrent glioblastoma may also be treated by surgical debulking with or without carmustine (BCNU) wafers, radiosurgery, nitrosoureas such as BCNU or lomustine (CCNU), or other single agent therapies such as carboplatin. A wide range of targeted agents are also in clinical trials. Te following are regimens that have been used both in the adjuvant setting and for patients who have recurrence after surgery, IFR, or both.
b. Regimens for newly diagnosed malignant glioma
(1) Temozolomide (TMZ) is administered differently depending upon whether it is being used in combination with IFR or not.
TMZ is dosed at 75 mg/m2 daily, 7 days per week, when given concurrently with IFR, for the entire duration of radiation. Trimethoprim-sulfamethoxazole should be administered thrice weekly with the daily temozolomide as prophylaxis against Pneumocystis jiroveci pneumonia.
TMZ is dosed at 150 to 200 mg/m2 by mouth daily for 5 consecutive days in a 28-day treatment cycle when given alone.
Administration of TMZ using a 21-day on followed by 7-day off schedule, a strategy aimed at overcoming resistance by depleting MGMT, has been compared with standard 5 days on, 23 days off TMZ in the postradiation setting for newly diagnosed GBM in a randomized study of 1153 patients but results are not yet available. Until then, 5-day per month TMZ remains the standard of care, regardless of a patient's MGMT methylation status.
(2) PCV is a combination of three antineoplastic agents given in a 6-week cycle:
Lomustine 110 mg/m2 by mouth on day 1
Vincristine 1.4 mg/m2 (maximum 2 mg) intravenously (IV) on days 8 and 29
Procarbazine 60 mg/m2 by mouth days 8 through 21 of the 42-day cycle
PCV is typically administered for 6 to 12 months or until tumor progression. PCV is associated with more myelotoxicity and neurotoxicity than other commonly prescribed chemotherapeutic drugs for malignant glioma.
c. Regimens for recurrent GBM
(1) Bevacizumab is administered at a dose of 10 mg/kg IV every 2 weeks. Dose reductions may be required, most commonly for hypertension or proteinuria. When given in combination with irinotecan, the dose of bevacizumab remains the same and irinotecan is dosed at 340 mg/m2 for patients on enzyme-inducing anticonvulsants and 125 mg/m2 for patients not on enzyme-inducing anticonvulsants.
(2) BCNU maybe administered as monotherapy and is given in either one dose or in two to three divided consecutive daily doses for a total of 150 to 200 mg/m2 IV every 6 weeks.
(3) BCNU wafers are a depot source of BCNU that can be surgically implanted at the time of resection. Te FDA approved the 3.85% BCNU wafer for recurrent GBM after a phase III, double-blind, placebo-controlled clinical study involving 222 patients undergoing surgery for recurrent malignant glioma showed that BCNU wafers increased median survival from 20 to 28 weeks. A second randomized trial was conducted using BCNU wafers at the time of initial diagnosis of malignant glioma and led to FDA approval for newly diagnosed malignant glioma. This study showed a median survival of 13.9 months in the BCNU wafer group versus 11.6 months in the placebo arm. However, when anaplastic and nonglial histologies were excluded from the analysis, a survival advantage for patients with GBM was not observed.
3. Oligodendroglioma (WHO grades II and III)
a. Characteristics. Low-grade (WHO grade II) oligodendroglioma (LGO) and anaplastic (WHO grade III) oligodendrogliomas (AO) are glial tumors that are found almost exclusively in the cerebral hemispheres and represent 4% to 15% of all gliomas. The peak incidence occurs in the fourth through sixth decades of life. Oligodendrogliomas have increased cellularity with homogeneous, hyperchromatic nuclei surrounded by clear cytoplasm: the classic “fried-egg” appearance. Allelic loss of the short arm of chromosome 1p and the long arm of chromosome 19q occurs in 50% to 70% of both AO and LGO and predicts better response to chemotherapy and longer survival. These tumors are hypointense on T1-weighted MRI scans and hyperintense on T2-weighted images and are located in the deep white matter. The median survival for WHO grade II oligodendrogliomas and WHO grade III oligodendrogliomas has been reported as 9.8 to 16.7 years and 3.5 to 5 years, respectively. However, these estimates do not stratify patients based on the underlying status of chromosomes 1p and 19q and patients with codeleted anaplastic oligodendroglioma have a median survival of 10 to 13 years in some series.
b. Treatment. Although the optimal treatment for these tumors remains controversial, the general approach is similar to that for astrocytomas. In all cases, if a tumor is suspected, a stereotactic biopsy should be performed or confirmed tumors should be resected, if feasible. Residual or unresectable LGOs can be followed with serial MRI studies and clinical examinations. As with low-grade astrocytomas, oligodendrogliomas with elevated MIB-1 labeling (> 3% to 5%) are considered higher risk and, therefore, are often treated like grade III tumors. Following the initial resection of an AO, radiation has been a standard recommendation. However, because grade III tumors have shown 60% to 100% response rates to PCV, this form of chemotherapy or temozolomide may be administered either prior to IFR or in the postradiation period. PCV has been shown to prolong disease-free survival but not overall survival in two randomized phase III trials in patients with AO. Temozolomide has shown a 31% objective response rate as initial therapy for LGO in patients with clinical and/or radiographic progression and no prior therapy other than surgery and a recent randomized study by Wick et al. in patients with anaplastic gliomas suggests that TMZ has comparable efficacy to PCV and is better tolerated.
C. Medulloblastoma (WHO grade IV)
1. Characteristics. Medulloblastomas are malignant embryonal tumors of the posterior fossa. Eighty percent are found in children under the age of 15 and this neoplasm accounts for 20% of all pediatric brain tumors. Medulloblastomas represent 1% of tumors in patients older than 20 years. Histologically, the tumor is characterized by poorly differentiated, densely packed, hyperchromatic, nucleated, small, round, blue cells. Medulloblastomas are invasive and tend to metastasize through the cerebral spinal fluid (CSF) to the rest of the CNS. The staging evaluation for these patients should include contrast-enhanced MRI of the entire neuraxis (brain and spinal cord) and lumbar puncture for CSF cytopathology if the latter can be safely performed. If disseminated disease is found at the time of the diagnosis (poor risk category), radical tumor resection confers little to no survival benefit.
2. Treatment. Treatment for local disease involves surgical resection, followed by craniospinal radiation (CSR) in adults to a dose of 36 Gy with a boost to the tumor bed to 54 Gy. In the average risk patient, this treatment approach is associated with a 60% 5-year progression-free survival. In an attempt to minimize the long-term side effects of radiation in children, one study reported acceptable results with 23.4 Gy of CSR given, with a boost to the tumor bed to 55.8 Gy, followed by cisplatin-based chemotherapy. This approach resulted in a 5-year progression-free survival of 79%.
There are multiple chemotherapy regimens for medullo-blastomas, all of which were developed in the pediatric population. A common approach involves the use of the following drugs in combination: etoposide, cisplatin, cyclophosphamide or CCNU, and vincristine. In patients with recurrent medullo-blastoma, high-dose chemotherapy with autologous stem cell rescue may be beneficial.
D. Primary central nervous system lymphoma in immunocompetent patients Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma arising within the CNS. This tumor accounts for 3.1% of all PBTs and the median age at diagnosis is 60. Ocular involvement is seen in 5% to 20% of cases and leptomeningeal spread in 20% to 40% of cases. Sixty percent of tumors are supratentorial and commonly involve the periventricular regions and corpus callosum. Twenty-five percent to fifty percent of cases have multifocal disease at the time of diagnosis. The lesions are hypointense to isointense on T1-weighted MRI and enhance homogeneously on postgadolinium images. The tumors are responsive to corticosteroids and, as a result, these drugs should be avoided until a diagnosis has been established. The only role for surgery in PCNSL is to establish the diagnosis by biopsy. These tumors should not be resected except in the rare circumstance of brain herniation from mass effect.
Extent of disease evaluations for patients with PCNSL should include gadolinium-enhanced MRI of the brain and spine; positron emission tomography-CT scan of chest, abdomen and pelvis; ophthalmologic evaluation with slit lamp examination; lumbar puncture for CSF cytopathology, flow cytometry, and immunoglobulin heavy gene rearrangement testing; serum lactate dehydrogenase level; and a bone marrow biopsy. Patients should also be tested for the human immunodeficiency virus.
Whole-brain radiation therapy (WBRT) results in a 90% response rate, but the median survival with WBRT alone is less than 12 months. PCNSL is sensitive to many types of chemotherapy, with all successful regimens involving the use of high-dose methotrexate (3.5 to 8 g/m2). Either alone or in combination with other hemotherapeutic drugs, methotrexate-based treatment is associated with radiographic response rates of 50% to 100% and survival durations of 40 to 90 months with or without the use of WBRT. The use of combination therapy is supported by a recent randomized phase 2 study of 79 patients with PCNSL showing significantly higher response rates with four courses of the combination of high-dose methotrexate and high-dose cytarabine compared with methotrexate alone (46% versus 18%, respectively).
Methotrexate 3.5 g/m2 day 1 and cytarabine 2 g/m2 every 12 hours on days 2 and 3. The first 0.5 g/m2 of the methotrexate is given over 15 minutes and the remaining 3 g/m2 is given over 3 hours with attention to alkalinization of the urine and maintenance of urine output of at least 100 mL/hour for the first 24 hours. Twenty-four hours after the start of the methotrexate infusion, leucovorin 25 mg is administered every 6 hours IV × 4, the oral for a total of 10 doses. Serum methotrexate levels should be followed and should fall by approximately 1 log per day. When the serum methotrexate concentration falls below 0.5 × 10-7 M (0.05 μM), the leucovorin maybe discontinued. Each cytarabine dose is given over 1 hour. Te regimen is repeated every 3 weeks for four courses.
Methotrexate is associated with potentially severe nephrotoxicity so renal function must be closely monitored during methotrexate treatment. Autologous stem cell transplantation may have a role for patients with chemosensitive disease either at first remission or at first relapse, but randomized trials are needed to determine whether survival is better than with standard-dose chemotherapy.
II. BRAIN METASTASES
Brain metastases are much more common than PBT in adults. The incidence is approximately 2.8 to 11.1 per 100,000 person-years in the United States. It is suspected that 20% to 25% of patients dying of cancer each year have brain metastases. Most commonly, cerebral metastases arise from cancer of the lung, breast, skin (melanoma), kidney, and colon.
1. Surgery. Because metastatic cancers often do not extensively infiltrate the surrounding normal brain parenchyma, these tumors can usually be resected without significant neurologic morbidity. However, this approach should be attempted only when the tumors are accessible and few in number, as revealed by CT or MRI, and when the patient's cancer is under good control systemically. In the 25% of all brain metastasis patients who have single or solitary lesions, surgery followed by WBRT results in longer survival than WBRT alone (40 versus 15 weeks for cerebral metastases from lung cancer).
2. Radiation therapy. WBRT is recommended for patients with brain metastases because micrometastatic disease is often present. Small brain metastases (generally 4 cm in diameter) that are solitary or persistent after WBRT may be treated with stereotactic radiosurgery (linear accelerator, cobalt source/gamma knife, proton radiosurgery). This technique uses a stereotactic frame and specialized external-beam focusing. It permits a high dose of radiation to be delivered to a small region in a single fraction. However, cerebral radiation necrosis is a potential complication and may necessitate either surgery or prolonged use of corticosteroids. The decision to proceed with either radiosurgery or resection should be individually tailored and based on status of the primary tumor, performance status, location of the tumor, and number of tumors. A randomized trial has shown that the addition of stereotactic radiosurgery (SRS) to WBRT increases survival in patients with single brain metastasis and achieves effective palliation in patients with one to three brain metastases. More recently, a randomized trial has shown that for patients with four or fewer brain metastases, the addition of WBRT to SRS improves intracranial disease control but does not alter overall survival compared with SRS alone. Limited neurocognitive testing in that trial suggested that intracranial disease progression rather than receipt of WBRT was the most important predictor of neurocognitive decline.
3. Chemotherapy. Chemotherapy has a limited role in the treatment of brain metastases. However, there are exceptions, because metastases from breast cancer occasionally respond well to the usual regimens for breast tumors. Lymphomatous brain masses may also respond to methotrexate-based chemotherapy.
III. LEPTOMENINGEAL METASTASES
The treatment of leptomeningeal metastases includes radiation therapy to symptomatic areas of the CNS (e.g., to the base of the brain for cranial nerve dysfunction or lumbosacral spine for cauda equina disease) and intrathecal (IT) chemotherapy with methotrexate, cytarabine (ara-C), or thiotepa.
A. Chemotherapy regimens
1. Methotrexate 12 to 15 mg per dose is the most commonly used IT chemotherapeutic agent. It is generally administered twice a week until the cytologic examination shows clearance of malignant cells from the CSF, then once a month as maintenance.
2. Cytarabine-liposomal 50 mg is a sustained-delivery form (DepoCyt, DepoFoam, Pacira Pharmaceuticals, San Diego, CA) of cytarabine for IT administration that allows treatment every 2 weeks. This is an advantage over conventional IT drugs, which must be delivered two to three times each week. Concurrent administration of oral corticosteroids (dexamethasone 4 mg twice a day on days 1 to 5) is required with the sustained-release form of cytarabine as the main side effect from this medication is arachnoiditis. Nonliposomal cytarabine can also be delivered intrathecally. Te most common dose is 30 mg/m2given every 4 days until normalization of spinal fluid.
3. Thiotepa 12 mg is a third IT chemotherapeutic agent that may be used if there is no response to methotrexate or cytarabine. However, the short CSF half-life of this agent may compromise its efficacy.
All chemotherapeutic agents for IT administration should be freshly prepared in preservative-free diluent. Because drugs that are administered into the lumbar subarachnoid space result in lower concentrations of the drugs in the upper spine and brain, it is advisable to administer these drugs through an Ommaya reservoir, a device that is implanted under the scalp and connected by a catheter, through a burr hole, to the frontal horn of the lateral ventricle. This method allows more reliable delivery of drug to the CSF and better distribution of drug along CSF pathways and avoids the necessity of repeated lumbar punctures for the patient.
Complications of IT chemotherapy include arachnoiditis and leukoencephalopathy. The latter is more likely to occur if the perforated tubing of the Ommaya catheter becomes lodged in brain tissue rather than the lateral ventricle. Myelosuppression is not usually significant unless the patient undergoes spinal irradiation or systemic chemotherapy as well. Oral leucovorin is generally given after IT methotrexate (10 mg leucovorin by mouth every 6 hours for six to eight doses, starting 24 hours after the methotrexate) to prevent bone marrow or mucous membrane toxicity.
IV. TREATMENT OF CEREBRAL EDEMA
These drugs are usually started soon after the diagnosis of a brain tumor is established. However, if PCNSL is suspected on the basis of the CT or MRI, then corticosteroids should be withheld until after a biopsy has been done. In the rare patient with PCNSL who requires emergent antiedema measures, mannitol may be administered (see later). Dexamethasone 10 mg IV followed by 4 mg every 6 hours by mouth or IV reduces or eliminates the lethargy, headaches, visual blurring, and nausea caused by cerebral edema and also often reduces some of the focal neurologic signs and symptoms such as hemiparesis. The corticosteroid dose should be tapered and discontinued after a complete surgical resection has been performed or after radiation therapy has been completed and resumed if symptoms recur. The dose should be held at the lowest dose that maximizes therapeutic benefit and minimizes side effects (e.g., gastric irritation, insomnia, mood swings, cushingoid body features, increased appetite, and myopathy).
B. Treatment of refractory cerebral edema
1. Increase dexamethasone. When moderate doses of dexamethasone do not effectively control cerebral edema, the dose maybe increased transiently up to 10 to 24 mg IV every 4 to 6 hours. This dose should usually not be maintained for longer than 48 to 72 hours.
2. An osmotic diuretic in an urgent situation may act more rapidly than a corticosteroid. Mannitol 75 to 100 g IV (as a 15%–25% solution) is given by rapid infusion over 20 to 30 minutes and repeated at 6 to 8 hours intervals as needed. Careful monitoring of electrolytes, serum osmolarity, fluid intake and output, and body weight is essential to avoid dehydration. The osmotic diuresis may be discontinued when there is improvement in the signs and symptoms from cerebral edema and when the corticosteroids or other measures to reduce cerebral edema have taken effect.
V. TREATMENT OF SEIZURES
Seizures are a common presenting feature in patients with brain tumors, with an incidence of approximately 20%. Prophylactic treatment for patients with brain tumors who have not had a seizure is not beneficial. However, it is common practice to administer a prophylactic anticonvulsant for a period of time after a biopsy or a craniotomy. If the patient has not had a seizure and has undergone only an uncomplicated biopsy or resection, the anticonvulsant may be discontinued after 4 to 8 weeks. If a patient does have a seizure and is to be placed on an anticonvulsant, levetiracetam is often recommended because is does not have cytochrome P-450 enzymeinducing properties that can influence chemotherapy metabolism. Alternative monotherapies include phenytoin, carbamazepine, oxcarbazepine, and valproic acid. If the patient has further seizures despite having sufficient serum levels of an anticonvulsant, then a second agent may be added. For those on long-term anticonvulsant therapy, it is important to check drug levels at intervals, especially after dosages of other medications have been changed or new medications have been added.
B. Common side effects
Common side effects of anticonvulsant treatment include sedation, nausea, rash, diplopia, dysmetria, ataxia, and hepatic dysfunction. A rare but serious toxicity is Stevens-Johnson syndrome, which is an immune complex–mediated hypersensitivity disorder. There may be an increased risk of this complication in patients undergoing simultaneous cranial irradiation and corticosteroid taper. This may present as a rash beginning as macules that may develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema. A fever is present in 85% of cases.
C. Cytochrome P-450 induction
Several commonly used anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may induce the hepatic cytochrome P-450 enzyme system with potentially important clinical implications. This may result in increased metabolism and reduced plasma levels of chemotherapeutic drugs that undergo hepatic metabolism. This has been demonstrated in a trial of the topoisomerase I inhibitor irinotecan (CPT-11) in patients with recurrent malignant gliomas. It was found that the maximum tolerated dose of CPT-11 was approximately fourfold higher in patients taking cytochrome P-450–inducing anticonvulsants than in patients not on these drugs. This emphasizes the importance of using anticonvulsants only when clearly indicated. Non-enzyme–inducing antiepileptic drugs include valproic acid, gabapentin, lamotrigine, levetiracetam, topiramate, and zonisamide (Table 15.1).
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