Chemotherapy for Brain Tumors
Leonard A. Farber, MD and John Chang, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2001
Authors: Irene V. Pech, MD, PhD, Neuro-Oncology Fellow, Department of Neurology and Neurological Sciences; Kendra Peterson, MD
Source: Oncology, April 1998, Volume 12, Number 4, pages 537-547
The treatment of adults and children with malignant brain tumors has incorporated the use of cytotoxic drugs with only a limited role. In addition, progress in the development of effective systemic chemotherapies has been slow, but improvements in the refinement of chemotherapeutic agents have occurred during the past decade. It is becoming evident that certain types of central nervous system (CNS) malignancies vary in their sensitivity to cytotoxic drugs. Primary CNS lymphoma, medulloblastoma, oligodendroglioma, and intracranial germ-cell tumors have been shown to be sensitive to chemotherapeutic agents.
In the article reviewed, the authors highlight advances in the chemotherapy of these tumors, as well as the potential use of both cytotoxic and cytostatic chemotherapy in other malignant brain tumors.
Primary CNS Lymphoma
Lymphomas of the brain parenchyma are usually of B-cell origin. Although once considered to be rare and occurring almost exclusively in older adults, they are now being diagnosed more frequently in younger patients and those with AIDS-associated chronic immunosuppression. Lesions are mostly intermediate- or high-grade, and may be single or multiple, and may involve any region of the CNS, including the cerebral hemispheres, cerebellum, brainstem, or spinal cord. Primary CNS lymphomas often are periventricular in location. Ocular involvement is a feature unique to CNS lymphomas, and may occur at diagnosis or subsequently develops in 20% of patients.
Many CNS lymphomas are sensitive to corticosteroids and rapid tumor lysis, presumably due to steroid-initiated apoptosis, is another unique feature of primary CNS lymphomas. They are radiosensitive, however, most patients die as a consequence of recurrent disease 12 to 18 months after initial treatment.
Methotrexate Among the most promising chemotherapeutic regimens is high-dose methotrexate. Neoadjuvant high-dose methotrexate has been shown to double median survival time for patients with primary CNS lymphoma from 12 to 8 months to more than 40 months.
Regimens Under Investigation First-line regimens for systemic lymphoma under evaluation include EDHAP (etoposide, dexamethasone, ara-C, and Platinol) and ADHAP (Adriamycin, dexamethasone, ara-C, and Platinol) followed by radiotherapy (with or without intrathecal methotrexate). In addition, regimens that incorporate better drugs for bulky disease but also treat the CSF and microscopic disease with intravenous and intrathecal methotrexate have been proposed.
Immunocompromised patients with CNS lymphoma generally respond poorly to chemotherapy and tolerate treatment poorly, as well. They often succumb to opportunistic infections.
Medulloblastomas of the cerebellum, while the most common CNS malignancy in children, account for less than 1% of adult brain tumors. They are histologically identical to neoplasms that arise elsewhere in the CNS called primitive neuroectodermal tumors (PNETs).
Treatment involves maximum safe resection, followed by staging. Staging includes a postoperative MRI or CT to assess residual tumor, a bone scan, a gadolinium-enhanced spinal MRI, and cytologic analysis of the CSF. At diagnosis, medulloblastomas occasionally have metastasized to bone or other extraneural structures, and commonly exhibit leptomeningeal seeding. The implication of CSF contamination is that with the exception of infants, the entire neuraxis is irradiated at diagnosis.
Craniospinal irradiation is curative in up to 50% of patients with medulloblastoma, however, not without significant toxic effects. Infants and young children are especially vulnerable to toxicities of treatment.
In adults, studies have shown a higher 5- and 10-year survival following adjuvant vincristine and CCNU, and in children, subset analysis of adjuvant trials with vincristine and CCNU suggested that patients with advanced-stage medulloblastoma may benefit from adjuvant chemotherapy.
Whole-neuraxis radiation alone is recommended for patients greater than 3 years of age with minimal residual tumor after surgery, and without evidence of CSF or systemic dissemination. These patients are considered to be at standard- or average-risk for recurrence.
Chemotherapy plus craniospinal irradiation is recommended for patients with bulky leptomeningeal or disseminated disease, who are know to be at high-risk for recurrence. Platinum based chemotherapy developed by Packer et al has also emerged as an adjuvant chemotherapy regimen for high-risk patients, demonstrating 5-year survival rates in excess of 85%.
For children less than 3 years old, chemotherapy is recommended and radiation delayed until the CNS in more fully matured.
A recent study analyzing a reduced neuraxis radiotherapy dose was closed early due to an increased risk of early relapse.
Oligodendrogliomas and mixed gliomas (i.e., oligoastrocytomas) account for 5% to 15% of glial tumors. They typically present with seizures in young and middle-aged adults, and may be low-grad and indolent or high-grade, i.e., anaplastic, and moderately aggressive. For patients with low-grade lesions, median survival exceeds 10 years, and for those with high-grade oligodendrogliomas median survival ranges from 2 to 5 years.
The mainstay of initial treatment is surgery, and oligodendrogliomas are frequently amenable to radical resection. Although postoperative radiotherapy was recommended for most patients with partially resected low-grade oligodendrogliomas and all patients with anaplastic tumors, some radiation oncologists may be becoming more conservative in their recommendations with earlier diagnosis by imaging emphasizing the indolent course of many oligodendrogliomas.
It has been know for many years that some gliomas respond to nitrosoureas. Studies by Cairncross and Macdonald demonstrated that recurrent anaplastic oligodendrogliomas respond to therapy with PCV (Procarbazine, CCNU, Vincristine). Others have reported that newly diagnosed aggressive tumors, mixed tumors, and symptomatic low-grade oligodendrogliomas may also respond to PCV. Oligodendrogliomas also have shown responses to other alkylators, including BCNU, CCNU, thiotepa, melphalan, dacarbazine, and cisplatin-containing regimens.
Germ-cell tumors of the CNS are rare cancer of children and young adults, the majority diagnosed in the second or third decade of life. Obstructive hydrocephalus and dorsal mid-brain compression account for the majority of symptoms. There are two types of germ-cell tumors of the CNS: germinomatous and nongerminomatous. The latter group includes choriocarcinomas, teratomas, yolk sac tumors, and endodermal sinus tumors. These tumors are histologically identical to germ-cell tumors arising in the gonads and mediastinum. They may secrete alpha-fetoprotein and beta-human chorionic gonadotropin.
These tumors frequently seed the leptomeninges, necessitating postoperative spinal MRI, CSF cytologic evaluation, and serum and CSF biochemistry for tumor markers. Pineal region tumors, such as these, are difficult to resect completely, but may be biopsied using MRI- or CT-guided sterotactic techniques.
Radiotherapy involving wide local-fields with or without spinal irradiation has been the mainstay of therapy. Germinomas are exquisitely radiosensitive and 5-year survival rates have been reported to be in excess of 80%. Nongerminomas are more refractory to radiation and are rarely cured by radiotherapy alone.
Single chemotherapeutic agents and combination regimens are currently in use. Responses to several have been reported. In patients with germinomas, remission up to 3 years have been reported with cisplatin-based regimens, and nongerminomatous tumors have been found to respond to cyclophophamide, cisplatin plus etoposide, and other platinum-based regimens.
Glioblastomas and Anaplastic Astrocytomas
Glioblastoma Multiforme (GBM) and anaplastic astrocytomas are the most common primary brain tumors of adults. The optima treatment schema includes maximum safe resection and radiotherapy. The extent of surgical resection is dictated largely by the location of the tumor. Nondominant frontal lobe tumors can be extensively debunked, whereas tumor in the basal ganglia or thalamus cannot.
Treatment with surgery and adjuvant radiation therapy prolongs like but is seldom curative. For patients with glioblastomas median survival is approximately 10 months, whereas for those with anaplastic astrocytomas, median survival is approximately 2 to 3 years.
With regards to chemotherapy, glioblastomas and anaplastic astrocytomas sometimes respond to BCNU, CCNU, and other nitrosoureas; procarbazine: and the new orally administered alkylating agent temozolomide. These tumors, however, tend to me substantially more resistant to chemotherapy than are lymphomas, medulloblastomas, oligodendrogliomas, or germ-cell tumors. Adjuvant chemotherapy with a nitrosurea or PCV has been show to increase 1- and 2-year survival rates in patients with GBM or anaplastic astrocytoma by up to 10%. Some believe that anaplastic astrocytomas are more responsive to chemotherapy than are GBMs and recommend adjuvant PCV for young patients with good performance status and intermediate-grade gliomas.
Ependymomas may occur at all levels of the neuraxis. Intracranial tumor are more common in children and usually found in the posterior fossa. Low-grade and anaplastic ependymomas may both occasionally seed the leptomeninges.
Treatment includes surgical removal if possible, spinal evaluation with MRI and CSF cytology, and limited-field radiation for localized tumors at diagnosis or craniospinal irradiation for disseminated disease.
The median duration of survival is 5 years for patients with intracranial disease. Poor prognostic indicators include young age, supratentorial location, incomplete resection, anaplastic pathology, and early dissemination.
For older children and adults, chemotherapy is not included in the standard initial therapy. It is being used increasingly to postpone irradiation in infants and young children.
Spinal ependymomas are more common in adults. Intramedullary spinal ependymomas tends to be circumscribed allowing surgical resection. Radiotherapy is recommended following incomplete resection. Myxopapillary ependymomas of the conus are more difficult to remove and may require radiotherapy, whole those occurring in the filum can often be resected completely and require no further treatment.There is no role for chemotherapy in the treatment of either intramedullary or myxopapillary spinal ependymomas.