The article by Pech and colleagues gives the medical oncologist an overview of the changing trends in the therapy of brain tumors. Patients often bring knowledge of these therapies to their clinicians after accessing easily-available Internet “brain tumor” Web sites or the user-friendly documents provided by such organizations as the Chicago-based American Brain Tumor Association. The initial evaluation of these individuals often includes a discussion of therapies, such as pre-irradiation chemotherapy, as well as “genetic therapies” that use replicating and nonreplicating viral vectors.

Although standard treatment for most primary brain tumors involves surgical resection, MRI- or CT-guided stereotactic biopsy is the sole procedure for patients of advanced age or for those with deep- seated or left hemispheric lesions associated with speech difficulty. Thereafter, chemotherapy, prior to radiation therapy, is administered to patients with drug-responsive tumors, such as primary CNS lymphoma in the immunocompetent patient, medulloblastoma or other primitive neuroectodermal tumors, benign or anaplastic oligodendrogliomas, mixed oligoastrocytomas, and atypical or malignant tumors of the pineal gland.

The use of drugs prior to irradiation or “up-front” reflects a desire to provide these agents during the period of maximal function that may occur following surgery. Later in the course of treatment, patients may experience profound alterations in quality of life, characterized by depression, apathy, and/or altered intellectual function, plus the adverse effects of cumulative doses of corticosteroids. As though this were not burdensome enough, the drugs administered at recurrence lose efficacy as a result of radiation-induced cerebral edema and phenytoin-induced cytochrome P450 isoenzymes. Hence, at least two-thirds of the chemotherapy agents provided through National Cancer Institute-sponsored consortiums for the treatment of brain tumors are given prior to, or concomitant with radiotherapy. For glioblastoma, these agents include camptothecin derivatives, biologic response modifiers, metalloproteinase inhibitors, modifiers of the hemoglobin-oxygen dissociation curve, and angiogenesis inhibitors. Future formulations include agents that provide slow release to or transiently disrupt the blood-brain barrier.

With the exception of malignant gliomas, the majority of studies reporting on chemotherapy for primary brain tumors are single-arm phase II trials. When available, randomized studies typically compare radiation alone to radiation with either pre-irradiation or adjuvant chemotherapy. The rapid introduction of new therapeutic agents and treatment approaches stymies the pursuit of phase III trials.

Emphasis should be placed, however, on drug therapy for three tumors: primary CNS lymphomas, medulloblastomas and other primitive neuro-ectodermal tumors, and malignant tumors containing foci of oligodendroglioma. In these malignancies, chemotherapy can reduce the size of the tumor and improve neurologic function.

Primary CNS Lymphoma
As the authors outline, methotrexate is a common denominator of successful chemotherapy regimens for primary CNS lymphoma. Interestingly, intravenous methotrexate monotherapy provides response rates and duration of responses comparable to those achieved with radiation/chemotherapy combination regimens.[1,2] At levels up to 8g/m2, methotrexate is well tolerated while still providing therapeutic drug concentrations to brain tissue and spinal fluid.[3,4] Concomitant administration of an intrathecal drug is then unnecessary, and the patient does not need an Ommaya reservoir. Methotrexate monotherapy has not been associated with the cognitive decline seen with radiation therapy nor with the uniform hematologic toxicity resulting from multiple drug combinations, such as methotrexate and CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone). The optimal methotrexate dose and dosing schedule still need to be determined.

Medulloblastoma
Oncologists treating adult medulloblastomas or similar pineoblastomas and malignant ependymomas may benefit from the experience of their pediatric colleagues. An example is the widespread use of the Packer et al regimen of adjuvant cisplatin (Platinol), lomustine (CCNU [CeeNu]), and vincristine, which improves durable responses over those achieved with radiation alone. Pre-irradiation multidrug combinations, including cisplatin, vincristine, etoposide, and cyclophosphamide (Cytoxan, Neosar), and the “eight-drugs-in-1-day” regimen have shown activity against medulloblastoma.[5,6] Preirradiation chemotherapy facilitates reduced radiation therapy doses and is associated with less apparent cognitive impairment than that resulting from drug therapy at tumor recurrence.

Oligodendroglioma
Anaplastic oligodendrogliomas, as well as malignant gliomas (anaplastic astrocytoma or glioblastoma), that contain small populations of oligodendroglial cells respond to chemotherapy. This field will change rapidly as specific markers for oligodendroglial cells are developed and as neuropathologists become familiar with the subtle histologic features of mixed tumors (oligoastrocytomas). As many as 20% of patients with malignant gliomas will be eligible to receive PCV (procarbazine, CCNU, and vincristine). Recipients of PCV potentially achieve reduced tumor mass and improved function and can then be given radiation therapy in reduced doses. Most patients tolerate only four drug cycles, however, creating a strong impetus to administer chemotherapy with marrow supportive techniques.