Editors: Skeel, Roland T.
Title: Handbook of Cancer Chemotherapy, 7th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 16 - Primary and Metastatic Brain Tumors
Primary and Metastatic Brain Tumors
April F. Eichler
Tracy T. Batchelor
I. Primary brain tumors (PBTs)
There were 43,800 malignant and benign PBTs diagnosed in the United States in 2005. An estimated 18,500 new cases of malignant brain and central nervous system (CNS) tumors were diagnosed in 2005, representing 1.35% of all malignant cancers and accounting for 12,760 deaths in the same year. The age-adjusted 5-year relative survival for all malignant PBTs from 1995 to 2000 was 32%. 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 40% 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. The more malignant types anaplastic astrocytoma and glioblastoma (GBM) are not curable, although each may respond to radiation therapy (RT) and chemotherapy. Astrocytomas are graded based on the presence or absence of the following histologic features: nuclear atypia, mitoses, endothelial proliferation, and necrosis.
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). Median survival is 7.5 years with a 5-year survival of 60%.
If feasible, a total resection should be performed and then the patient should be followed up regularly with serial MRI studies and clinical examinations. Randomized clinical trials have shown that there is no overall survival benefit when RT is given at the time of the original diagnosis, although progression-free survival may be improved with early RT. There is controversy regarding the management of WHO grade II astrocytoma in high-risk patients, for example, those of advanced age (>40 years) or with an elevated MIB-1 (a monoclonal antibody) labeling index (>3% 5%), as these tumors are more likely to progress rapidly. One option in this setting is to administer involved field radiation (IFR) up to 60 Gy.
In the event of tumor progression on computed tomography (CT) or MRI, further surgery, if possible, may be performed, and IFR is recommended. If, at the time of the recurrence, the histopathology demonstrates a higher-grade astrocytoma, chemotherapy can be initiated, which will be discussed in the next section on malignant astro-cytomas.
Grades III and IV Astrocytoma. Anaplastic astrocytoma (WHO grade III) occurs most commonly in the fourth and fifth decades, whereas GBM (WHO grade IV) occurs most commonly in the fifth and sixth decades. Median survival times are 24 to 36 and 9 to 12 months, respectively. These two types of tumors are indistinguishable by MRI, as both 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 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, IFR up to 60 Gy is given, usually in combination with chemotherapy. Positive prognostic factors include high Karnofsky performance score, gross total resection, and younger age.
Chemotherapy. Chemotherapy is now considered standard of care for glioblastoma since the publication 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 (RT 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, as compared with 12.1 months in the RT arm. In addition, the 2-year survival rate was 26% in the chemoradiation group as compared with 10% in the RT group. On the basis of these results, concurrent TMZ/RT followed by monthly TMZ has become the standard of care for patients with newly diagnosed GBM. Patients with anaplastic astrocytoma could be treated similarly, although randomized data using TMZ/RT for newly diagnosed grade III tumors does not yet exist. Onemechanism of resistance to alkylating agents is the deoxyribonucleic acid (DNA) repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Multiple studies have shown that alkylating agents are more effective when MGMT is inactivated by promoter methylation. However, routine determination of MGMT methylation status has not yet achieved widespread acceptance.
Chemotherapy regimens. TMZ, an imidotetrazine analogue of dacarbazine (DTIC), acts by methylating DNA. It has excellent oral bioavailability and relatively
Temozolomide 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/week, when given concurrently with IFR, for the entire duration of radiation.
Trimethoprim sulfamethoxazole should be administered thrice weekly with daily TMZ as prophylaxis against pneumocystis jiroveci (formerly carinii) pneumonia.
TMZ is dosed at 150 to 200 mg/m2 PO daily for 5 consecutive days in a 28-day treatment cycle when given alone.
Administration of TMZ using a 21-day-on 7-day-off schedule, a strategy aimed at overcoming resistance by depleting MGMT, has not proved to be of benefit and might be more toxic.
BCNU may be administered as adjuvant monotherapy and is given in either one dose or in 2 to 3 divided consecutive daily doses for a total of 150 to 200 mg/m2 IV every 6 weeks.
PCV is a combination of three antineoplastic agents given in a 6-week cycle:
Lomustine 110 mg/m2 PO on day 1
Vincristine 1.4 mg/m2 (maximum 2 mg) IV on days 8 and 29
Procarbazine 60 mg/m2 PO 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.
BCNU wafers are a depot source of BCNU that can be surgically implanted at the time of resection. The U.S. Food and Drug Administration (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
Recurrent malignant astrocytoma may be treated by surgical debulking, radiosurgery, or chemotherapy. In general, recurrent malignant gliomas are resistant to most types of therapy, and consideration of treatment within the context of a clinical trial is appropriate.
Oligodendroglioma (WHO grades II and III)
Characteristics. Low-grade (WHO grade II) oligodendroglioma (LGO) and anaplastic (WHO grade III) oligodendrogliomas (AOs) 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 years, respectively. However, these estimates do not stratify patients on the basis of the underlying status of chromosomes 1p and 19q.
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 up with serial MRI studies and clinical examinations. As with low-grade astrocytomas, oligodendrogliomas with elevated MIB-1 labeling (>3% 5%) are considered higher risk and, therefore, are often treated like grade III tumors. Following the initial resection of an AO, RT has been a standard recommendation. However, since grade III tumors have shown 60% to 100% response rates to PCV, this form of chemotherapy or TMZ is administered either before 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. TMZ 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.
C. Medulloblastoma (WHO grade IV)
Characteristics. Medulloblastomas are malignant embryonal tumors of the posterior fossa. Eighty percent are found in children younger than 15 years, 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 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.
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 chemotherapy. This approach resulted in a 5-year progression-free survival of 79%.
There are multiple chemotherapy regimens for medulloblastomas, all of which were developed in the pediatric population. A common approach involves the use of the following drugs in combination: etoposide, cisplatin, cyclophosphamide, and vincristine. In patients with recurrent medulloblastoma, high-dose chemotherapy with autologous stem cell rescue may be beneficial.
D. Primary central nervous system lymphoma (PCNSL) in immunocompetent patients
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 50% 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; CT scans of chest, abdomen and pelvis; ophthalmologic evaluation with slit lamp examination; lumbar puncture for CSF cytopathology, flow cytometry and IgH (immunoglobulin
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 8 g/m2). Either alone or in combination with other chemotherapeutic drugs, methotrexate-based treatment is associated with radiographic response rates of 50% to 100% and survival durations of 40 to 90 months without the use of WBRT. Methotrexate is associated with potentially severe nephrotoxicity; so renal function must be closely monitored during methotrexate treatment.
II. Brain metastases
Brain metastases are much more common than PBT in adults. The incidence is approximately 2.8 to 11.1/100,000 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.
Surgery. Because metastatic cancers often do not extensively infiltrate the surrounding normal brain parenchyma, these tumors can usually be resected. 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 brain metastases patients who have single or solitary lesions, surgery followed by WBRT results in longer survival than WBRT alone (40 vs. 15 weeks for cerebral metastases from lung cancer).
Radiation therapy. WBRT is recommended for patients with brain metastases as micrometastatic disease is often present. Small brain metastases (generally less than 4 cm in diameter) that are solitary or persistent after WBRT may be treated with stereotactic radiosurgery (SRS) (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 RT 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 SRS to WBRT increases survival in patients with single brain metastasis and achieves effective palliation in patients with one to three brain metastases.
Chemotherapy. Chemotherapy has a limited role in the treatment of brain metastases. However, there are exceptions, as metastases from breast cancer occasionally respond well to the usual regimens for breast tumors.
III. Leptomeningeal metastases
The treatment of leptomeningeal metastases includes RT to symptomatic areas of the CNS (e.g., to the base of the brain for cranial nerve dysfunction) and intrathecal (IT) chemotherapy with methotrexate, cytosine arabinoside (ara-C), or thiotepa.
A. Chemotherapy regimens
Methotrexate, 12 to 15 mg/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, and then once a month as maintenance.
Cytarabine (ara-C) 50 mg is available in a sustained-delivery form (Depocyt, Depotec, depofoam) 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 b.i.d. 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 ara-C can also be delivered intrathecally. The most common dose is 30 mg/m2 given every 4 days until normalization of spinal fluid.
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. Since 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 in 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 PO every 6 hours for six to eight doses, starting 24 hours after the methotrexate) to prevent bone marrow 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 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
B. Treatment of refractory cerebral edema
Increase dexamethasone. When moderate doses of dexamethasone do not effectively control cerebral edema, the dose may be 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.
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
A. 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, phenytoin (Dilantin) at 300 mg/day is often recommended. Alternative monotherapies include carbamazepine, oxcarbamazepine, and valproic acid. Newer broad-spectrum anticonvulsants, such as levetiracetam (Keppra), are unproven for monotherapy but potentially of value in the future. 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.
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
Table 16.1. Antiepileptic drugs, enzyme-inducing versus nonenzyme-inducing
C. Cytochrome P-450 induction
Several commonly used anticonvulsants (phenytoin, phenobarbital, 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 16.1).
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