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.
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. 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-sensitivea 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.
After recurrent CNS lymphomas were observed to respond dramatically to methotrexate(Drug information on methotrexate), CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone), CHOD (cyclophosphamide, doxorubicin HCl, Oncovin, and dexamethasone(Drug information on dexamethasone)), BACOD (bleomycin, Adriamycin, cyclophosphamide(Drug information on cyclophosphamide), Oncovin, and dexamethasone) and PCV (procarbazine, CCNU, and vincristine), cytotoxic agents were added to radiotherapy and prescribed at diagnosis.[4-7]
High-Dose MethotrexateAlthough 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 and Neuwelt et al. 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(Drug information on mannitol). Chamberlain et al also have reported median survival times in excess of 40 months in patients treated with hydroxyurea plus radiation followed by PCVanother CNS-penetrating formula.
Regimens Under InvestigationFirst-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.
Immunocompromised patients with CNS lymphoma may benefit from chemotherapy, but most respond poorly, tolerate treatment poorly, or succumb to opportunistic infections. 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 ChemotherapyIt 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. Hence, regimens that do not include radiation therapy are especially valuable for older patients.