Chemotherapy for Brain Tumors

Gradually, the treatment of adults and children with malignant brain
tumor is improving. Structural and functional MRI and intraoperative
cortical and subcortical mapping studies in awake patients are
leading to safer, more complete resections, and, for most types of
brain tumor, complete resection is associated with a substantially
better outcome.

As a consequence of CT- and MRI-guided stereotactic biopsy,
unresectable tumors can be sampled safely and a precise diagnosis
established in most instances. This greater diagnostic accuracy may
lead, in some cases, to the selection of specific, more effective
postoperative therapies.

New radiation therapy techniques, such as three-dimensional conformal
radiotherapy and fractionated stereotactic radiotherapy, by limiting
the volume of normal brain tissue irradiated, lessen the risk and
severity of delayed neurotoxicity without sacrificing the
tumor-controlling benefits of higher doses of radiation. In selected
patients, stereotactic radiosurgery and interstitial radiotherapy
(brachytherapy) permit intensive irradiation of small tumors in
noneloquent regions of the brain. These methods enhance tumor control
with acceptable or manageable toxic effects.

With regard to medical management, the growing network of
sophisticated physicians (eg, oncologists, pediatricians,
neurologists) cognizant of the special problems and needs of adults
and children with cancers of the nervous system, together with the
emergence of multidisciplinary brain tumor treatment centers, is
enhancing patient care.

Traditionally, cytotoxic drugs have had a limited role in the
treatment of patients with malignant brain tumor, and progress in the
development of truly effective systemic chemotherapies has been slow.
However, important advances in the chemotherapy of malignant brain
tumors have occurred during the past decade. In much the same way
that surgical and radiotherapeutic techniques have become
increasingly refined, so, too, has chemotherapy.

It is now evident that the many types of central nervous system (CNS)
malignancies differ in their response to cytotoxic drugs and that
some CNS tumors, such as primary CNS lymphoma, medulloblastoma,
oligodendroglioma, and intracranial germ-cell tumors, are remarkably
chemosensitive. Within 10 years, it is likely that several classes of
malignant brain tumor will be treated initially, primarily, or
exclusively with systemic chemotherapy.

This article will highlight advances in the chemotherapy of brain
tumors, focusing on the chemosensitive CNS malignancies, but also
will include some data on the potential use of cytotoxic and
cytostatic chemotherapeutic agents in other, less
“chemosensitive” tumors, such as glioblastomas and
anaplastic astrocytomas. Lastly, a discussion of future directions
that may hold promise, including high-dose chemotherapy with
stem-cell rescue, blood-brain barrier disruption, and regional
treatment using controlled-release biodegradable polymers, is included.

Primary CNS Lymphoma

Lymphomas of the brain parenchyma, usually of B-cell origin, were
once considered rare tumors that occurred almost exclusively in older
adults (ie, in patients > 60 years old). Now, however, they are
being diagnosed increasingly in younger patients and those with
iatrogenic or AIDS-associated chronic immunosuppression.

An extensive search for an occult systemic lymphoma is unwarranted in
most instances of CNS lymphoma, as these intermediate- or high-grade
lymphomas rarely arise or spread systemically. Lesions may be single
or multiple and may involve any region of the CNS, including the
cerebral hemispheres, cerebellum, brainstem, or spinal cord.

In an immunocompetent patient, the typical primary CNS lymphoma
appears on MRI or CT as a discrete homogeneously enhancing lesion
with little peritumoral edema or displacement of adjacent structures
(ie, mass effect). In immunocompromised patients, particularly those
with AIDS, CNS lymphomas may be nonenhancing or have other atypical
radiographic features.

Primary CNS lymphomas often are periventricular in location, and, not
surprisingly, at diagnosis neoplastic lymphocytes are found in the
cerebrospinal fluid (CSF) in approximately one-third of cases.[1]
Primary CNS lymphomas restricted to the leptomeninges also have been
described. Ocular involvement is a unique feature of CNS lymphoma
(not seen with other primary CNS malignancies), which occurs at
diagnosis or subsequently in 20% of patients.

Surgery is essential for diagnosis but has little therapeutic role in
this diffusely infiltrating, multifocal neoplastic process.

Many CNS lymphomas, perhaps 40%, are exquisitely
corticosteroid-sensitive—a property that is advantageous
therapeutically but can complicate the diagnostic process. Large
tumors may regress completely in the time it takes to organize a
stereotactic biopsy procedure. [2,3] If a primary CNS lymphoma is
suspected, clinically or radiographically, and the patient is stable,
corticosteroids should be withheld until the day of surgery,
otherwise there may be no target for the surgeon or the tissue
retrieved may be necrotic or nondiagnostic. Rapid tumor lysis,
presumably via a steroid-initiated apoptotic cell death pathway, is
another unique feature of primary CNS lymphoma.

These tumors also are radiosensitive, and for many years whole-brain
radiotherapy was the standard treatment. Radiation alone produced a
complete clinical and radiographic response in 80% of patients.
Although responsive to radiotherapy, most patients with primary CNS
lymphoma died as a consequence of recurrent disease 12 to 18 months
after initial treatment. Rare young immunocompetent patients with
lymphoma enjoyed long-term survival with steroids and whole-brain
radiation therapy, but serious neuropsychological and neuroendocrine
toxicities due to radiation meant that permanent tumor control
sometimes came at a high price.

Chemotherapy
After recurrent CNS lymphomas were observed to respond dramatically
to methotrexate, CHOP (cyclophosphamide, doxorubicin HCl, Oncovin,
and prednisone), CHOD (cyclophosphamide, doxorubicin HCl, Oncovin,
and dexamethasone), BACOD (bleomycin, Adriamycin, cyclophosphamide,
Oncovin, and dexamethasone) and PCV (procarbazine, CCNU, and
vincristine), cytotoxic agents were added to radiotherapy and
prescribed at diagnosis.[4-7]

High-Dose Methotrexate—Although no standard
chemotherapeutic regimen has emerged, among the most promising
regimens is high-dose methotrexate. Methotrexate is neurotoxic in
irradiated patients, causing a leukoencephalopathy, but is safe and
effective when given neoadjuvantly. Neoadjuvant high-dose
methotrexate has doubled the median survival time for patients with
primary CNS lymphoma from 12 to 18 months to more than 40 months.

Two patterns of failure may account for the particular success of the
methotrexate-based chemotherapeutic strategies of DeAngelis et al[8]
and Neuwelt et al[9]. First, early recurrences at distant brain sites
have occurred with regimens that do not contain CNS-penetrating drugs
(eg, CHOP, CHOD, and BACOD). Second, leptomeningeal recurrences have
developed when initial treatment does not include intrathecal chemotherapy.[1,10,11]

Thus, early treatment of subclinical, subradiographic, microscopic
lymphoma behind an intact blood-brain barrier, remote from bulky
lesions, and early treatment of the CSF compartment may be essential
components of regimens with curative potential. DeAngelis et al use
drugs that, except for vincristine, cross the blood-brain barrier and
give intrathecal methotrexate (Table 1),
while Neuwelt et al ensure drug delivery to the brain and CSF by
transiently disrupting the blood-brain barrier with mannitol.
Chamberlain et al[12] also have reported median survival times in
excess of 40 months in patients treated with hydroxyurea plus
radiation followed by PCV—another CNS-penetrating formula.

Regimens Under Investigation—First-line regimens for
systemic lymphoma, such as EDHAP (etoposide, dexamethasone, ara-C,
and Platinol) or ADHAP (Adriamycin, dexamethasone, ara-C, and
Platinol) followed by radiotherapy (with or without intrathecal
methotrexate), are under evaluation. Two studies have examined drug
combinations with superior antilymphoma activity but inferior brain
and CSF penetration (CHOP and CHOD) followed by whole-brain
radiation.[13,14] No improvement in survival was found over radiation
therapy alone, and toxicity from chemotherapy was a significant problem.

Regimens that incorporate better drugs for bulky disease but also
treat microscopic disease and the CSF compartment with intravenous
and intrathecal methotrexate have been proposed.[15]

Immunocompromised patients with CNS lymphoma— may benefit
from chemotherapy, but most respond poorly, tolerate treatment
poorly, or succumb to opportunistic infections.[16] The role of
chemotherapy for AIDS-related CNS lymphoma may evolve in the future
as more effective therapies for the primary infection enable patients
to live longer and tolerate more aggressive antineoplastic treatment.

Current Role of Chemotherapy—It is likely that
radiotherapy will be held in reserve for increasing numbers of
patients with primary CNS lymphoma as medical oncologists strive to
develop curative systemic regimens. Indeed, many complete responders
to chemotherapy and elderly patients are now being treated with
cytotoxic drugs alone.[11,17] Late sequelae of radiation therapy are
a significant problem in the elderly, with radiation-induced dementia
(occurring as early as 1 year after treatment) of particular
concern.[8] Hence, regimens that do not include radiation therapy are
especially valuable for older patients.