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
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
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
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, 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 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.
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.
1. DeAngelis LM, Yahalom J, Heinemann MH, et al: Primary CNS
lymphoma: Combined treatment with chemotherapy and radiotherapy.
Neurology 40:80-86, 1990.
2. Freilich RJ, DeAngelis LM: Primary central nervous system
lymphoma. Neurol Clin 13:901-914, 1995.
3. Geppert M, Ostertag CB, Seitz G, et al: Glucocorticoid therapy
obscures the diagnosis of cerebral lymphoma. Acta Neuropathol
4. Kawakami Y, Tabuchi K, Ohnishi R: Primary central nervous system
lymphoma. J Neurosurg 62:522-527, 1985.
5. Loeffler JS, Ervin TJ, Matich P, et al: Primary lymphomas of the
central nervous system: Patterns of failure and factors that
influence survival. J Clin Oncol 3:490-494, 1985.
6. Pollack IF, Lunsford LD, Flickinger JC, et al: Prognostic factors
in the diagnosis and treatment of primary central nervous system
lymphoma. Cancer 63:939-947, 1989.
7. Gabbai AA, Hochberg FH, Linggood R: High dose methotrexate therapy
of primary brain lymphoma. J Neurosurg 70:190-194, 1988.
8. DeAngelis LM, Yahalom J, Thaler HT, et al: Combined modality
treatment for primary CNS lymphoma. J Clin Oncol 10:635-643, 1992.
9. Neuwelt EA, Goldman DL, Dahlborg SA, et al: Primary CNS lymphoma
treated with osmotic blood-brain barrier disruption: Prolonged
survival and preservation of cognitive function. J Clin Oncol
10. Stewart DJ, Russell N, Dennery M, et al: Cyclophosphamide,
Adriamycin, vincristine and dexamethasone in the treatment of bulky
CNS lymphomas. J Neurooncol 2:289, 1984.
11. Cher L, Glass J, Harsh GR, et al: Treatment of primary CNS
lymphoma with methotrexate-based chemotherapy and deferred
radiotherapy: Preliminary results. Neurology 46:1757-1759, 1996.
12. Chamberlain MC, Levin VA: Primary central nervous system
lymphoma: A role for adjuvant chemotherapy. J Neurooncol 14:271-275, 1992
13. Lachance DH, Brizel DM, Gockerman JP, et al: Cyclophosphamide,
doxorubicin, vincristine, and prednisone for primary central nervous
system lymphoma: Short-duration response and multifocal intracerebral
recurrence preceding radiotherapy. Neurology 44:1721-1727, 1994.
14. Schultz C, Scott C, Sherman W, et al: Preirradiation chemotherapy
with cyclophosphamide, doxorubicin, vincristine, and dexamethasone
for primary CNS lymphomas: Initial report of Radiation Therapy
Oncology Group protocol 88-06. J Clin Oncol 14:556-564, 1996.
15. DeAngelis LM: Current management of primary central nervous
system lymphoma. Oncology 9:63-71, 1995.
16. Forsyth, PA, Yahalom J, DeAngelis LM: Combined modality therapy
in patients with primary central nervous system lymphoma in AIDS.
Neurology 44:1473-1479, 1994
17. Freilich RJ, Delattre JY, Monjour A , et al: Chemotherapy without
radiation therapy as initial treatment for primary CNS lymphoma in
older patients. Neurology 46:435-439, 1996
18. Hubbard JL, Scheithauer BW, Kispert DB, et al: Adult cerebellar
medulloblastoma: The pathological, radiographic and clinical
spectrum. J Neurosurg 70:536-544, 1989.
19. Cohen ME, Duffner PK: Medulloblastomas, in Cohen ME, Duffner PK
(eds): Brain Tumors in Children, 2nd ed, pp 177-201. New York, Raven
20. Wisoff JH, Epstein FJ: Management of pediatric brain tumors, in
Morantz RA, Walsh JW (eds): Brain Tumors; A Comprehensive Text, pp
581-611. New York, Marcel Dekker, 1993.
21. Friedman HS, Oakes WJ, Bigner SH, et al: Medulloblastoma: Tumor
biological and clinical perspectives. J Neurooncol 11:1-15, 1991.
22. Tait DM, Thorton-Jones H, Bloom HJ, et al: Adjuvant chemotherapy
for medulloblastoma: The first multi-centre control trial of the
International Society of Pediatric Oncology (SIOP I). Eur J Cancer
23. Evans AE, Jenkin DT, Sposto R, et al: The treatment of
medulloblastoma: Results of a prospective randomized trial of
radiation therapy with and without CCNU, vincristine and prednisone.
J Neurosurg 72:572-582, 1990.
24. Bloom HJG, Bessell EM: Medulloblastoma in adults: A review of 47
patients between 1952 and 1981. Int J Radiat Oncol Biol Phys
25. Packer RJ, Sutton LN, Elterman R, et al: Outcome for children
with medulloblastoma treated with radiation and cisplatin, CCNU, and
vincristine chemotherapy. J Neurosurg 81:690-698, 1994.
26. Deutsch M, Thomas PR, Krischer J, et al: Results of a prospective
randomized trial comparing standard dose neuraxis irradiation (3600
cGy/20) with reduced neuraxis irradiation (2340 cGy/13) in patients
with low-stage medulloblastoma: A combined Childrens Cancer
Group-Pediatric Oncology Group study. Pediatr Neurosurg 24:167-176, 1996.
27. Shaw EG, Scheithauer BW, OFallon JR, et al:
Oligodendrogliomas: The Mayo Clinic experience. J Neurosurg
28. Cairncross JG, Macdonald DR: Successful chemotherapy for
recurrent malignant oligodendroglioma. Ann Neurol 23:360-364, 1988.
29. Levin VA, Edwards MS, Wright DC, et al: Modified procarbazine,
CCNU and vincristine (PCV-3) combination chemotherapy in the
treatment of malignant brain tumors. Cancer Treat Rep 64:237-241, 1980.
30. Cairncross G, Macdonald D, Ludwin S, et al: Chemotherapy for
anaplastic oligodendroglioma. J Clin Oncol 12:2013-2021, 1994
31. Glass J, Hochberg FH, Gruber ML, et al: The treatment of
oligodendrogliomas and mixed oligodendrogliomas-astrocytomas with PCV
chemotherapy. J Neurosurg 76:741-745, 1992.
32. Cairncross JG, Macdonald DR, Ramsay DA: Aggressive
oligodendroglioma: A chemosensitive tumor. Neurosurgery 31:78-82, 1992.
33. Macdonald DR, Gaspar LE, Cairncross JG: Successful chemotherapy
for newly diagnosed aggressive oligodendroglioma. Ann Neurol
34. Brown M, Cairncross JG, Vick NA et al: Differential response of
recurrent oligodendrogliomas versus astrocytomas to intravenous
melphalan. Neurology 40(suppl):397-398, 1990.
35. Poisson M, Pereon Y, Chiras J, et al: Treatment of recurrent
malignant supratentorial gliomas with carboplatin (CBDCA). J
Neurooncol 10:139-144, 1991.
36. Saarinen UM, Pihko H, Makipernaa A: High-dose thiotepa with
autologous bone marrow rescue in recurrent malignant
oligodendroglioma: A case report. J Neurooncol 9:57-61, 1990.
37. Kyritsis AP, Yung WKA, Bruner J, et al: The treatment of
anaplastic oligodendrogliomas and mixed gliomas. Neurosurgery
38. Allen JC: Controversies in the management of intracranial germ
cell tumors. Neurol Clin 9:441-452, 1991.
39. Kida Y, Kobayashi T, Yoshida J, et al: Chemotherapy with
cisplatin for AFP-secreting germ-cell tumors of the central nervous
system. J Neurosurg 65:470-475, 1986.
40. Allen JC, Bosl G, Walker R: Chemotherapy trials in recurrent
primary intracranial germ cell tumors. J Neurooncol 3:147-152, 1985.
41. Patel SR, Buckner JC, Smithson WA, et al: Cisplatin-based
chemotherapy in primary central nervous system germ cell tumors. J
Neurooncol 12:47-52, 1992.
42. Castaneda VL, Parmley RT, Geiser CF, et al: Postoperative
chemotherapy for primary intracranial germ cell tumor. Med Pediatr
Oncol 18:299-303, 1990.
43. Allen JC, Helson L: High-dose cyclophosphamide chemotherapy for
recurrent CNS tumors in children. J Neurosurg 55:749-756, 1981.
44. Kobayashi T, Yoshida J, Ishiyama J, et al: Combination
chemotherapy with cisplatin and etoposide for malignant intracranial
germ-cell tumors: An experimental and clinical study. J Neurosurg
45. Packer RJ, Sutton LN, Rorke LB, et al: Intracranial embryonal
cell carcinoma. Cancer 54:520-524, 1984.
46. Balmaceda C, Heller G, Rosenblum M, et al: Chemotherapy without
irradiationA novel approach for newly diagnosed CNS germ cell
tumors: Results of an international cooperative trial. J Clin Oncol
47. Fine HA, Dear KBH, Loeffler JS, et al: Meta-analysis of radiation
therapy with and without chemotherapy for malignant gliomas in
adults. Cancer 71:2585-2597, 1993.
48. Levin VA, Silver P, Hannigan J, et al: Superiority of
post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine and
vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final
report. Int J Radiat Oncol Biol Phys 18:321-324, 1990.
49. Friedman SH, Oakes WJ: The chemotherapy of posterior fossa tumors
in childhood. J Neurooncol 5:217-229, 1991.
50. Inamura T, Nomura T, Bartus RT, et al: Intracarotid infusion of
RMP-7, a bradykinin analog: A method for selective drug delivery to
brain tumors. J Neurosurg 81:752-758, 1994.
51. Kleinschmidt-DeMasters BK, Geier JM: Pathology of high-dose
intra-arterial BCNU. Surg Neurol 31:435-443, 1989.
52. Shapiro WR, Green GB, Burger PC, et al: A randomized comparison
of intra-arterial versus intravenous BCNU, with or without
intravenous 5-fluorouracil, for newly diagnosed patients with
malignant glioma. J Neurosurg 76:772-781, 1992.
53. Brem H, Domb A, Lenartz D, et al: Brain biocompatibility of a
biodegradable controlled release polymer consisting of anhydride
copolymer of fatty acid and sebacic acid. J Control Rel 19:325-330, 1992.
54. Domb A, Bogdansky S, Olivi A , et al: Controlled delivery of
water soluble and hydrolytically unstable anti-cancer drugs for
polymeric implants. Polymer Preprints 32:219-220, 1991.
55. Brem H, Piantadosi S, Burger PC, et al: Intraoperative controlled
delivery of chemotherapy by biodegradable polymers: Safety and
effectiveness for recurrent gliomas evaluated by a prospective,
multi-institutional placebo-controlled clinical trial. Lancet
56. OReilly SM, Newlands ES, Glaser MG, et al: Temozolomide: A
new oral cytotoxic chemotherapeutic agent with promising activity
against primary brain tumors. Eur J Cancer 29A:940-942, 1993.