Chemotherapy for Brain Tumors

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.