Treatment of Meningeal Malignancy

STACEY L. BERG, DAVID G. POPLACK

Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas, USA

Key Words. Cancer · Meninges · Chemotherapy · Ommaya · Intrathecal · Brain tumor · Cerebrospinal fluid

A BSTRACT
Meningeal metastasis from cancer has become an increas-
ingly frequent problem as the treatment of systemic dis-
ease improves. Leukemia, lymphoma and solid tumors
may all metastasize to the meninges, where the blood-brain
barrier may provide a sanctuary from cytotoxic concen-
trations of chemotherapeutic agents. Because meningeal
requires administration of either very high drug doses or
prolonged infusions in order to overcome the poor pene-
tration of most anticancer agents into the central nervous
system. Thus, systemic toxicity is often a major drawback
to this approach. Intrathecal chemotherapy results in
delivery of anticancer agents directly into the cerebro-

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disease may be clinically silent or may present with
unusual signs and symptoms, it is important to maintain a
high index of suspicion for this problem. Diagnosis is usu-
ally made by cerebrospinal fluid cytologic testing, mag-
netic resonance imaging, or both. Treatment options
include radiation therapy, systemic chemotherapy and
intrathecal chemotherapy. Systemic therapy usually
spinal fluid, usually with minimal systemic toxicity.
Intrathecal chemotherapy may be administered by lum-
bar puncture or by use of an Ommaya reservoir with the
tip in the ventricle. Studies are under way to evaluate new
agents for both systemic and intrathecal administration.
Further research is required to overcome this difficult
clinical challenge. The Oncologist 1996;1:56-61

INTRODUCTION which flows in the subarachnoid space between the pia and
Meningeal malignancy presents a difficult clinical chal- the arachnoid, may then provide a route for metastasis
lenge for both pediatric and adult oncologists. As improve- along the entire neuraxis. Leukemia, brain tumors and other
ments in systemic therapy have resulted in longer survival for solid tumors may all metastasize to the meninges and
patients with various malignancies, the incidence of meningeal spread in this fashion (Table 1).
metastasis has increased. This is probably due to the “sanctu- Prior to the institution of CNS preventive therapy, meningeal
ary” effect created by the blood-brain barrier, which prevents leukemia occurred in more than 50% of children with acute lym-
many anticancer drugs from achieving cytotoxic concentra- phoblastic leukemia (ALL), and the CNS was the most common
tions in the central nervous system (CNS). In this article, site of relapse in patients who achieved bone marrow remissions.
advances in the treatment of meningeal disease will be pre- The current strategies for preventive therapy have decreased the
sented, including both incidence of CNS leukemia to less than 10%, although relapses
new agents and new still occur and may be difficult to treat. Meningeal leukemia also
Table 1. Some tumors that may metastasize to
the meninges approaches to the use occurs in adults: based on autopsy series, meningeal involvement
of standard agents. may occur in 25% to 81% of cases [1, 2].
▲ Leukemia
Meningeal malig- CNS involvement is common in non-Hodgkin’s lym-
▲ Lymphoma
nancy results from the phomas. Solid tumors also metastasize to the meninges.
▲ Melanoma
metastasis of intracra- In adults, the tumors most commonly responsible are carcino-
▲ Carcinoma (especially breast, lung) nial or extracranial mas of the lung, breast and gastrointestinal tract,
▲ Ewing’s sarcoma tumors to the lep- and melanoma [3]. In children, rhabdomyosarcoma, Ewing’s
▲ Rhabdomyosarcoma tomeninges (the arach- sarcoma and retinoblastoma may metastasize to the CNS. Brain
▲ Retinoblastoma noid membrane and the tumors such as gliomas, medulloblastomas, ependymoblas-
▲ Brain tumors pia mater). The cere- tomas, germinomas and choroid plexus carcinomas, as well
brospinal fluid (CSF), as primary CNS lymphoma, may also spread to the meninges.

Correspondence: Stacey L. Berg, M.D., Texas Children’s Hospital, 6621 Fannin Street, MC3-3320, Houston, TX 77030,
USA. Telephone: 713-770-4588; Fax: 713-770-4202. Accepted for publication October 23, 1995. ©AlphaMed Press 1083-
7159/96/$5.00/0

The Oncologist 1996;1:56-61

Berg, Poplack
DIAGNOSIS
Meningeal cancer may be clinically silent. Therefore, in
diseases like leukemia in which meningeal spread is com-
mon, “surveillance” of the CSF with periodic lumbar punc-
tures is often undertaken. Because of such surveillance,
CNS leukemia is now usually diagnosed before it becomes
symptomatic. In other cases, the clinical picture of
meningeal metastasis may be nonspecific. The most com-
mon signs and symptoms of meningeal malignancy are
those of increased intracranial pressure. Headache is most
common, although cranial nerve and spinal cord symptoms
are also frequent [4]. Unusual signs such as sudden hearing
loss or complex partial seizures may also occur. Thus, it is
important to keep meningeal malignancy in mind when
patients with cancer present with any neurologic complaints.
The diagnosis of meningeal metastasis is usually made
by examination of the CSF. For solid tumors, the presence
of malignant cells in the CSF confirms the diagnosis. For
leukemias, the combination of malignant blasts and an ele-
vated cell count is usually required. The significance of
leukemic blasts in the presence of a normal CSF white
blood cell count is uncertain [5-7]. In some cases where
meningeal malignancy is suspected, repeated lumbar punc-
tures may be required to identify malignant cells. This is
especially true for solid tumors. Even so, however, in 90%
of cases the diagnosis can be confirmed by three or fewer
CSF examinations [8]. The diagnostic role of tumor markers
in the CSF has not yet been established.
Radiographic evaluation may sometimes be helpful in the
evaluation of patients with suspected meningeal disease.
Computerized tomography (CT) scanning is relatively insensi-
tive, but magnetic resonance imaging (MRI), especially with
gadolinium enhancement, may be more helpful. Many false
negative and some false positive results do occur with MRI,
however. In addition, 111Indium-DTPA flow studies may show
abnormalities of CSF flow, although these studies are usually
used as part of treatment planning prior to intrathecal therapy
rather than as a diagnostic tool. A combination approach
using both CSF studies and radiographic modalities is often
appropriate in patients with suspected meningeal disease.
TREATMENT
Both chemotherapy and radiation therapy may be used in
the prevention or treatment of meningeal malignancy. Cranial
irradiation is part of many regimens to prevent the develop-
ment of meningeal leukemia, especially in high-risk patients,
and craniospinal irradiation is usually employed as part of the
therapy for meningeal relapse. Radiation therapy, however,
may result in both short- and long-term toxicity. Craniospinal
radiotherapy often causes significant myelosuppression,
which may complicate efforts to administer systemic
57
anticancer therapy. Cranial irradiation may produce the
“somnolence syndrome,” which consists of a prodrome of
irritability and anorexia followed by a variable period of
somnolence. Recovery is spontaneous, and the somnolence
syndrome is not predictive of later complications of therapy.
Long-term complications of cranial or craniospinal
irradiation may include second malignancies, short stature,
growth hormone abnormalities and hypothyroidism.
Cortical atrophy, IQ deficits and leukoencephalopathy may
also occur. Younger children are more vulnerable to the
long-term toxicities of radiation therapy than are older chil-
dren [9]. The trend in leukemia therapy is toward reduced
doses (e.g., 1800 cGy) of neuraxis radiation. In other child-
hood tumors, the minimal dose of radiation adequate for
tumor control, as well as strategies for delaying radiation
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therapy in younger children, are under active study.
The chemotherapeutic approach to meningeal cancer
can be divided into systemic (intravenous or oral) and
regional (intrathecal or intraventricular) therapy; both have
advantages and disadvantages. Systemic administration
may produce more uniform drug distribution throughout
the CNS, and prolonged intravenous infusion may produce
cytotoxic CSF drug concentrations for a prolonged period.
Most systemically administered agents, however, do not
cross the blood-brain barrier well, and systemic toxicity
limits the ability to treat meningeal disease by this route. In
contrast, intrathecal drug administration may produce cyto-
toxic concentrations in the CSF even when small doses are
used, and systemic toxicity is very rare. However, lumbar
punctures may be difficult, drugs may not be delivered into
the intrathecal space and drug distribution in the CSF may
be uneven. The use of an Ommaya reservoir to deliver
drugs directly into the ventricular CSF overcomes some of
these problems, but use of this device requires special
expertise as well as a neurosurgical procedure for place-
ment. In addition, neurotoxicity may occur after direct
administration of drugs into the CSF.
In the following section, specific agents used in the
treatment of CNS malignancy will be discussed. Tables 2
and 3 present some typical doses and schedules for these
agents, but should not be construed as recommendations for
treatment of individual patients.
METHOTREXATE
Intrathecal methotrexate has been used in the treatment
of meningeal leukemia since the 1950s. Intrathecal
methotrexate either given alone or in combination with
other agents can prevent the development of meningeal
leukemia in 90% of children. Furthermore, intrathecal
methotrexate often provides effective CNS reinduction
therapy for meningeal relapse [10-12].
 58 Treatment of Meningeal Malignancy

Although methotrexate is detectable in plasma after an

Table 2. Some systemically administered agents that have been investigated
for the treatment of meningeal malignancy intrathecal administration, systemic toxicity is not usually a
problem after an intrathecal dose. However, acute or delayed
Standard Agents Dose Schedule Reference neurotoxicity is relatively common after intrathecal methotrex-
Methotrexate 33 g/m2 24-h infusion Balis, 1985 ate administration. Chemical arachnoiditis, manifested by
Cytarabine 1-3 g/m 2 q 12 h × 6 Frick, 1984 headache, back pain, meningismus, fever, vomiting and a CSF
Thiotepa 65 mg/m2 single dose Heideman, 1989 pleocytosis, may occur hours to days after methotrexate
administration and is usually self-limited [15]. In severe cases,
Investigational Agents Dose Schedule Reference oral corticosteroids may improve symptoms. On rare occa-
6-mercaptopurine 50 mg/m2/h 36-h infusion Adamson, 1990 sions, transient or permanent weakness or paraplegia may
Topotecan phase I studies occur following intralumbar administration of methotrexate.
under way This unusual toxicity may be related to delayed clearance of
methotrexate from the CSF resulting in high CSF methotrex-
ate levels [16]. Late neurotoxicity in the form
Table 3. Some intrathecally administered agents that have been investigated for the treatment of of leukoencephalopathy may also occur,

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meningeal malignancy usually in patients who have received intra-
venous methotrexate and cranial irradiation
Standard Agents Dose Schedule Reference
in addition to intrathecal methotrexate [17].
Methotrexate IT <1 year of age: 6 mg single dose Bleyer, 1977 Inadvertent overdoses of intrathecal
1 year of age: 8 mg Bleyer, 1983
2 years of age: 10 mg methotrexate can be fatal. Immediate treat-
≥3 years of age: 12 mg ment including ventriculostomy with ven-
triculo-lumbar perfusion, administration of
IT systemic corticosteroids and administration
2 mg daily × 3 Bleyer, 1978
(“C × T”)
of systemic leucovorin may be beneficial
[18]. In addition, intrathecal administration of
Cytarabine IT 24-70 mg single dose Blaney, 1991
IT carboxypeptidase-G2 has been shown to res-
15 mg daily × 3 Blaney, 1991
(“C × T”) cue nonhuman primates from experimental
intrathecal methotrexate overdose [19], and
Thiotepa IT 10 mg single dose Grossman, 1993 may play a role in the treatment of accidental
intrathecal overdose in humans.
Investigational Agents Dose Schedule Reference In patients with recurrent meningeal
Diaziquone IT 1 mg twice weekly Berg, 1992 disease, intrathecal methotrexate therapy is
IT often given through an indwelling Ommaya
0.5 mg q6h×3 Berg, 1992
(“C × T”) reservoir. Intraventricular administration
through a reservoir results in a more even
6-mercaptopurine IT 10 mg single dose Adamson, 1991
distribution of drug throughout the CSF
Mafosfamide/4HC IT phase I studies and may prolong the duration of remission
under way in CNS leukemia compared to intralumbar
administration [20, 21]. In addition, the use
Topotecan IT phase I studies of the Ommaya reservoir permits the
under way administration of frequent small doses of
methotrexate instead of single large doses.
This “concentration times time” (C × T)
Because the CSF volume approaches adult size years therapy produces cytotoxic concentrations for a prolonged
before body surface area does, the dose for intrathecal period while avoiding high peak drug levels.
methotrexate is based on patient age, with a constant dose Intravenous administration of methotrexate is also used
administered to all patients over three years of age. This in the treatment of meningeal disease. Although the CSF:
approach both reduces toxicity in older patients and plasma ratio for methotrexate is low, cytotoxic methotrexate
improves outcome in younger patients [13, 14]. Because of concentrations can be attained in the CSF using very high
these observations, most other intrathecal agents in children intravenous doses. One such high-dose methotrexate regimen
are also dosed based on age rather than body size. consisting of a 6000 mg/m2 loading dose given over 1 h,
Berg, Poplack
followed immediately by an infusion of 1200 mg/m2/h for
23 h resulted in cytotoxic steady-state CSF methotrexate
concentrations and produced complete remissions in 16 of
20 children with meningeal relapse of ALL [22].
High-dose systemic methotrexate administration
requires both intense hydration and alkalinization of
urine, and leucovorin rescue. Since methotrexate is elimi-
nated by the renal tubule, adequate renal function should
be confirmed prior to therapy, and serum creatinine and
methotrexate concentrations should be monitored during
therapy. If delayed clearance is encountered, intravenous
hydration and leucovorin rescue should be increased. At
methotrexate concentrations greater than 10-4 mol/l, how-
ever, leucovorin rescue may be ineffective [23]. In the
presence of acute renal failure with severely delayed
methotrexate excretion, administration of carboxypepti-
dase-G2 may be considered. The use of this enzyme
results in a greater than 10-fold reduction of serum
methotrexate concentrations within minutes of adminis-
tration [24]. Information about the availability of car-
boxypeptidase for emergency use can be obtained from
the National Cancer Institute.
Even with normal methotrexate clearance and ade-
quate hydration and leucovorin rescue, toxicity after high-
dose methotrexate is frequent. Moderate to severe
mucositis and myelosuppression are common. Hepatic tox-
icity with elevated transaminases and bilirubin, as well as
desquamating dermatitis of the hands and feet, can also
occur. High-dose methotrexate, especially when given in
association with cranial radiation, has also been associated
with neurotoxicity [25, 26].
CYTARABINE
Intrathecal cytarabine is used frequently in the treat-
ment of meningeal metastasis. As with methotrexate, high
CSF cytarabine concentrations with negligible systemic
toxicity can be achieved by intrathecal cytarabine admin-
istration. Like methotrexate, cytarabine may be given by
the intralumbar route or through a ventricular reservoir on
a C × T schedule that results in cytotoxic CSF drug con-
centrations for a prolonged period without high peak lev-
els [27]. In addition, cytarabine is often combined with
methotrexate for intrathecal administration, especially in
patients with leukemia.
Intrathecal administration of cytarabine may produce
arachnoiditis or, rarely, other forms of neurotoxicity such as
seizures and paraplegia [28]. Cytarabine therapy, however,
has not been associated with leukoencephalopathy.
Cytarabine may also be administered systemically for
the treatment of meningeal malignancy. A regimen of 3 g/m2
administered every 12 h demonstrated activity in patients
59
with meningeal leukemia [29], and 72-h continuous
intravenous infusions of ≥4 g/m2 also achieved cytotoxic
CSF cytarabine concentrations [30]. High-dose systemic
cytarabine administration is associated with significant
toxicity, however. Cerebellar dysfunction requiring dis-
continuation of therapy may be seen in >20% of patients
following multiple doses of 3 g/m2 every 12 h [31]. Myelo-
suppression, nausea, vomiting and mucositis are also
common at these doses.
CORTICOSTEROIDS
Prednisone (the orally administered prodrug of pred-
nisolone) and dexamethasone are widely used in the ther-
apy of ALL. For both, the CSF concentrations are identical
to the plasma concentrations of free drug. Since at equipo-
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tent doses dexamethasone is only 70% protein bound,
whereas 90% of prednisolone is bound, dexamethasone
penetrates much better into the CSF [32]. Patients receiving
dexamethasone rather than prednisone have a significantly
lower rate of CNS relapse [33].
THIOTEPA
Thiotepa, a lipid-soluble alkylating agent, crosses the
blood-brain barrier well after systemic administration.
Furthermore, TEPA, an active metabolite of thiotepa,
also penetrates very well into the CSF [34, 35]. Thus, sys-
temic administration of this agent achieves high concen-
trations of both parent drug and active metabolite in the
CSF. Systemic administration of thiotepa, however, pro-
duces profound bone marrow toxicity, especially throm-
bocytopenia. In contrast, intrathecal administration of
thiotepa is well tolerated [36]. However, intrathecal
administration of thiotepa may have some disadvantages
compared to the systemic route. The active metabolite
TEPA is not detected in the CSF after intrathecal admin-
istration. Furthermore, thiotepa diffuses rapidly out of the
CSF space [34]. Nonetheless, intrathecal thiotepa may be
useful in some settings.
DIAZIQUONE
Diaziquone (AZQ) was specifically developed for its
property of excellent CSF penetration after systemic
administration. Unfortunately, severe myelosuppression
limits the utility of this approach. Intrathecal diaziquone,
however, is well tolerated at a dose of 1 mg administered
twice weekly by either the intralumbar or intraventricular
route and at a C × T dose of 0.5 mg every 6 h for three
doses. More than 65% of patients had an objective response
to this therapy, and two of four patients with meningeal
spread of retinoblastoma had complete responses of three
months’ duration [37].
60
6-MERCAPTOPURINE
6-mercaptopurine is commonly used in low oral doses
as an antileukemic agent. Recent studies have shown that a
48-h intravenous infusion of 6-mercaptopurine at a dose
rate of 50 mg/m2/h achieves cytotoxic concentrations in the
CSF. The common toxicities include reversible hepatotoxi-
city, myelosuppression and mucositis [38]. Intrathecal
administration of 6-mercaptopurine is also being explored.
In children with refractory meningeal malignancy, a 10 mg
intrathecal dose was well tolerated and produced cytotoxic
concentrations in the CSF for over 12 h. Of nine patients
treated at the 10 mg dose, there were four complete and
three partial responses [39].
OTHER NEW AGENTS
Studies are under way with intrathecal administration of two
preactivated derivatives of cyclophosphamide: mafosfamide
and 4-hydroperoxycyclophosphamide (4HC). These agents
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