Intra-CSF administration of chemotherapy medications

REVIEW ARTICLE

Intra-CSF administration of chemotherapy medications

Michael P. Gabay • Jigisha P. Thakkar •

Joan M. Stachnik • Susan K. Woelich •

J. Lee Villano

Received: 19 December 2011 / Accepted: 11 May 2012 / Published online: 3 June 2012

� Springer-Verlag 2012

Abstract Leptomeningeal carcinomatosis is a devastating

complication of cancer and is likely increasing in inci-

dence. The combination of widespread neuro-axial spread

based on CSF flow and the blood–brain barrier (BBB) has

favored immediate local delivery of antineoplastic agents.

With the BBB, the leptomeninges can be a sanctuary site to

systemic cancers and goal of therapy includes preventing

involvement in this space. Current therapies with U.S.

Food and Drug Administration (FDA) approval are limited

to treat hematologic cancers. Although lacking FDA

guidance, a wider array of therapies is available to treat

solid tumors. We provide an updated examination on

both well-established intra-CSF chemotherapies as well as

agents having limited data, but reports of therapeutic

benefit.

Keywords Leptomeningeal carcinomatosis �Chemotherapy � Intrathecal � Neoplastic meningitis

Introduction

Leptomeningeal carcinomatosis (LMC), also termed neo-

plastic meningitis, occurs when cancer involves the pia

matter covering the brain and spine and the arachnoid

membrane. Within this area, malignant cells are thought to

disseminate throughout the neuro-axis by passive cerebro-

spinal fluid (CSF) flow. Patients can present with a range of

neurologic symptoms including pain, and outcomes are

generally poor. The incidence of LMC is likely increasing

with prolonged survival of patients with primary malig-

nancies and advances in diagnostic imaging technology [1].

With increased survival, there is a greater interval of time

for disease to recur in the central nervous system (CNS) as

many chemotherapeutic agents have poor penetration

through the blood–brain barrier (BBB). LMC is estimated to

occur in 3–8 % of all patients with cancer [1]. It is diag-

nosed in 1–5 % of patients with solid tumors, 5–15 % of

patients with leukemia and lymphoma, and 1–2 % of

patients with primary brain tumors [2]. The most common

solid tumors spreading to leptomeninges are breast cancer

(43 %), lung cancer (31 %), and melanoma (6 %) [3].

Among hematologic malignancies, LMC is most commonly

seen in acute lymphoid leukemia (ALL), acute myeloid

leukemia (AML), and high grade lymphomas (Burkitt’s,

large cell) [4]. LMC usually represents a terminal event

with median survival ranging from 2 to 6 months [3]. Most

untreated patients with LMC from solid tumors die within

3–6 weeks due to progressive neurologic dysfunction [3, 5].

Magnetic resonance imaging (MRI) with and without

gadolinium enhancement (Gd-MRI), as well as CSF analy-

sis, is commonly used for diagnosis of LMC. For LMC in

leukemia and lymphoma, monoclonal antibodies for

immunohistochemical analysis can be used to distinguish

between reactive and neoplastic lymphocytes in the CSF [6].

M. P. Gabay � J. M. Stachnik � S. K. Woelich

Department of Pharmacy Practice, University of Illinois at

Chicago, Chicago, IL 60612, USA

J. P. Thakkar � J. L. Villano (&)

Department of Medicine, Section of Hematology/Oncology,

University of Illinois at Chicago, 840 S. Wood St. M/C 713,

Chicago, IL 60612, USA

e-mail: [email protected]; [email protected]

Present Address:S. K. Woelich

HealthCare Milwaukee, Milwaukee, WI 53219, USA

Present Address:J. L. Villano

University of Kentucky, 800 Rose St. CC 447, Lexington,

KY 40536, USA

123

Cancer Chemother Pharmacol (2012) 70:1–15

DOI 10.1007/s00280-012-1893-z

Cytogenetic studies (i.e., flow cytometry and DNA single-

cell cytometry) and fluorescence in situ hybridization can

give additional diagnostic information. These techniques are

especially useful in liquid tumors (leukemia and lymphoma)

and appear more sensitive than CSF cytology [7–9].

To assess therapeutic response in LMC, evaluation of

the combination of neurologic and overall clinical status as

well as CSF cytology and imaging [2] are used. Objective

evaluation of LMC treatment is challenging. Clinical and

CSF cytology changes generally predate imaging findings,

and CSF cytology evaluation has low sensitivity. Conver-

sion from positive to negative cytology or cytometry is

considered a response and suggests continuation of therapy

[2]. CSF obtained from a site distant from pathologically

involved meninges may not correlate with disease presence

or therapeutic response; emphasis should be placed on

examining CSF from sites of clinical or neuroradiographic

disease [10, 11]. A single negative CSF cytology is

insufficient to indicate treatment response and this finding

should be confirmed by subsequent CSF analysis [12, 13].

Quantitative CSF cytology should also be considered to

assess partial response to LM-directed therapies [14].

Biochemical markers, immunohistochemistry, and molec-

ular biology techniques applied to CSF have been explored

in an attempt to find a reliable biological marker of disease.

These biochemical markers when followed serially can

help assess response to treatment [2].

Treatment

Therapy for LMC is not standardized and is largely palli-

ative, rarely curative. Management requires a multidisci-

plinary approach including therapies described in the

following sections and supportive measures. Treatment

goals include maintenance or improvement in quality of

life by neurologic stabilization, prevention from further

neurologic deterioration, and improvement of survival [2].

Surgery and radiotherapy (RT)

Surgery and radiotherapy (RT) are employed for palliation.

Surgery involves immediate treatment for hydrocephalus.

This can be an external ventricular drain, and if therapeu-

tic, placement of a ventriculo-peritoneal (VP) shunt [15].

Rarely is surgery performed to remove bulky disease.

Radiation therapy helps to decrease symptoms at sites of

bulky disease where intra-CSF chemotherapy is limited by

diffusion to 2–3 mm. Radiation therapy is also beneficial

for palliation of cauda-equina syndrome and cranial neur-

opathies from LMC [3]. Involved field RT to the site of

CSF flow obstruction restores flow in 30–50 % of patients

and when followed by intra-CSF chemotherapy, leads to

longer survival duration than patients who have persistent

blocks [3].

Systemic chemotherapy

When symptoms require systemic treatment, the neuro-axis

can also improve [15]. LMC from solid tumors is well

vascularized and enhances on imaging scans with contrast

material, which demonstrates that the BBB is not fully

intact. A limitation of intra-CSF therapy is sites of bulky

LMC that prevent normal CSF flow, which systemic ther-

apy can overcome [3].

Intra-CSF therapy

Intra-CSF therapy is used for treatment and prevention of

LMC from both solid and hematologic tumors [1]. Intra-CSF

therapy includes injection of the chemotherapeutic agent by

either lumbar puncture (intrathecal (IT)) or intraventricular

Ommaya reservoir/Chemoport [1, 16]. It is designed to treat

tumor cells in the CSF, thereby preventing the development

of new sites of disease [5]. Intra-CSF treatment offers local

therapy with minimum systemic toxicity, bypasses the blood

brain and blood CSF barriers, and allows for more uniform

distribution and therapeutic levels of drugs in the subarach-

noid space [3]. As discussed previously, a limitation of intra-

CSF therapy is impaired or obstructed CSF flow in the

presence of bulky meningeal disease [3, 15, 17].

Timing

In many patients, multimodality treatment can be consid-

ered and therapy is generally administered in sequence. On

the basis of concerns of neurotoxicity, radiation therapy

generally follows intravenous chemotherapy with intra-

CSF chemotherapy administered subsequently. Although

the data are limited and older, it has become established not

to administer intra-CSF therapies concurrently with radia-

tion therapy due to increased neurotoxicity [3, 18].

Standard agents for CNS administration

Methotrexate

Methotrexate, along with cytarabine, is one of the more

common chemotherapeutic agents administered via the

intrathecal route. The drug is approved for use in a variety

of neoplastic diseases, psoriasis, and rheumatoid arthritis

including polyarticular-course juvenile rheumatoid arthritis

[19]. For prophylaxis or treatment of meningeal leuke-

mia, methotrexate has FDA-approved intrathecal dosing

(Table 1). The preservative-free formulation of the drug

2 Cancer Chemother Pharmacol (2012) 70:1–15

123

should be diluted to a concentration of 1 mg/mL and

dosing is based upon age not body surface area. Metho-

trexate may be given every 2–5 days for treatment;

however, administration at intervals of less than every

7 days may result in increased toxicity. The drug should be

given until CSF cell count normalizes. One additional dose

should be administered once this goal is achieved. Beyond

the label, other effective intrathecal methotrexate dosage

regimens are available in the published literature for both

prophylaxis and treatment in adults and children [20]. Dose

reduction may be required in elderly patients as CSF

volume and turnover decreases with age. While strict dose

reductions may not be needed, concerns of increased

toxicity should be considered in patients having renal

impairment, third space fluid accumulation, and on certain

medications, specifically NSAIDS. In addition, caution is

advisable in situations where systemic methotrexate is

administered concurrently with intra-CSF therapy. Con-

comitant administration may result in increased toxicity

and potentially leucovorin rescue.

When given via the intralumbar route, methotrexate is

eliminated in a biphasic manner (e.g., initial half-life of

4.5 h and terminal half-life of 14 h) [21]. Mean metho-

trexate CSF levels decrease substantially within 24 h of a

single intralumbar dose: [10 lmol/L at 6 h to 0.1 lmol/L

at 24 h. In contrast, levels following ventricular metho-

trexate administration were consistently higher after a

single dose: [200 lmol/L to 0.2 lmol/L at 48 h. In addi-

tion, intraventricular administration has been associated

with a significantly longer duration of CNS remission.

Elimination of methotrexate from the CSF is primarily

through CSF bulk flow excretion with some non-specific

active transport also occurring. Accumulation of metho-

trexate can occur in systemic tissues following intrathecal

administration with highest concentrations seen in the liver,

kidney, lymph nodes, and spleen [22]. Intrathecal metho-

trexate doses, when compared to equivalent oral or intra-

venous doses, result in plasma concentrations 10-fold

higher 24 h after administration. In addition, the extent of

absorption (AUC) in plasma of methotrexate is 20–30

times greater with intrathecal versus systemic administra-

tion of an equivalent dose.

Administration of intrathecal methotrexate has been

associated with various safety issues, with neurotoxicity a

primary concern. Methotrexate-related neurotoxicity is

usually classified into 3 categories: acute, subacute, and

chronic [23]. Intrathecal methotrexate may result in acute

chemical arachnoiditis (headache, nausea, vomiting, fever,

back pain, and dizziness) within 2–4 h after administration.

This occurs in 5–40 % of patients given intrathecal

methotrexate and generally lasts for 12–72 h. Subacute

neurotoxicity generally occurs days to weeks following

methotrexate exposure and may take the form of encepha-

lopathy or severe myelopathy (leg pain, sensory changes,

paraplegia, and bladder dysfunction). Recovery from

symptoms usually occurs spontaneously after 48–72 h.

Chronic neurotoxicity occurs months to years following

therapy with the most common clinical presentation being

leukoencephalopathy involving confusion, somnolence or

irritability, impaired vision and speech, seizures, ataxia, and

dementia. Severe cases can result in quadriparesis, coma, or

death. Multiple case reports have been published illustrating

the neurotoxic effects of intrathecal methotrexate [24–31].

Beyond neurotoxic effects, intrathecal methotrexate therapy

has been reported to be linked to a variety of other serious

adverse events including acute tumor lysis syndrome [32],

acute respiratory distress syndrome [33, 34], hematologic

toxicity [35], and pneumonitis [36].

Overview of clinical data

There are multiple published clinical studies involving the

administration of intrathecal methotrexate for CNS pro-

phylaxis and treatment. Kwong and colleagues recently

reviewed the use of intrathecal chemotherapy for hemato-

logic malignancies [20]. With regard to prophylactic use of

intrathecal methotrexate (either alone or in combination with

other intrathecal treatments) in children with acute lym-

phoblastic leukemia, included studies found a 5- to 6-year

event-free survival rate between 70 and 82 %. Within these

studies, CNS relapse ranged from 1.8 to 9.5 %. In adults,

event-free survival rates were lower across the selected

studies—24 % at 3 years up to 52 % at 5 years. Only a few

adult studies reported CNS relapse rates (3–4 %).

Few active comparator trials of intrathecal methotrexate

have been performed; however, Glantz and colleagues

compared intrathecal sustained-release cytarabine to

intrathecal methotrexate in patients with neoplastic

meningitis from solid tumors [37]. In this prospective,

open-label, multicenter study, 61 adult patients were ran-

domly assigned to receive either sustained-release cytara-

bine 50 mg or methotrexate 10 mg for induction and

consolidation therapy. Enrollees could receive up to 6

doses of sustained-release cytarabine or up to 16 doses of

methotrexate over 3 months. Overall, response rates were

similar: 26 % for sustained-release cytarabine versus 20 %

for methotrexate; p = 0.76. Median survival from

Table 1 Approved intrathecal

methotrexate dosage regimens

for Meningeal Leukemia [19]

Age (years) Dose (mg)

\1 6

1 8

2 10

3 or older 12

Cancer Chemother Pharmacol (2012) 70:1–15 3

123

randomization was also similar (105 days cytarabine vs.

78 days methotrexate; p = 0.16). Sustained-release cyt-

arabine was associated with an improved median time to

neurologic progression (58 days vs. 30 days; p = 0.007).

Adverse events were comparable between the 2 therapies.

Kim and colleagues evaluated the efficacy of intrathecal

methotrexate alone versus a combination of intrathecal

methotrexate, cytarabine, and hydrocortisone in patients with

leptomeningeal carcinomatosis of a solid tumor [38]. Fifty-

five patients were included in this retrospective study.

Twenty-nine patients were given intrathecal methotrexate

15 mg and 26 received the same dose of intrathecal metho-

trexate with hydrocortisone 15 mg/m2 and cytarabine 30

mg/m2. Therapy was administered twice weekly initially with

responders (i.e., those showing no malignant or atypical cells

in the CSF) receiving weekly maintenance therapy. Cyto-

logical response was significantly improved in the combina-

tion intrathecal therapy arm as compared to intrathecal

methotrexate alone (38.5 vs. 13.8 %; p = 0.036). Neurologic

response was not significantly different between treatments

(73.1 % combination vs. 58.6 % methotrexate; p = 0.26).

Median survival was prolonged in the combination arm

(18.6 weeks vs. 10.4 weeks; p = 0.029). Treatment-related

toxicities were similar for both arms with no hematologic or

non-hematologic adverse events over Grade 3 reported.

Hitchins and colleagues compared intrathecal methotrex-

ate monotherapy to a combination of intrathecal methotrexate

and cytarabine in 44 patients with non-leukemic meningeal

carcinomatosis [39]. Twenty-two patients were administered

intrathecal methotrexate 15 mg and 20 received the same

dose of intrathecal methotrexate with cytarabine 50 mg/m2.

A majority of enrolled patients (n = 32) also received

100 mg of hydrocortisone before each treatment to minimize

arachnoiditis. During the initial week, patients received

treatments every other day. Patients that responded continued

treatment for 3 weeks and received maintenance therapy if

the response persisted. Results revealed an overall response

rate of 55 % with 7 patients experiencing a complete

response. Patients randomized to methotrexate alone had a

non-significantly higher response rate as compared to com-

bination therapy (61 % vs. 45 %; p [ 0.1). In addition,

administration of medications via an Ommaya reservoir was

associated with an improved response as compared to lumbar

puncture (65 % vs. 48 %; p [ 0.1). Overall median survival

was 8 weeks. Again, median survival was improved with

methotrexate monotherapy, but not to a significant degree (12

vs. 7 weeks; p = 0.084).

Cytarabine and cytarabine liposome (depot)

Cytarabine, a nucleoside analog of deoxycytidine, is

thought to act through the inhibition of DNA polymerase,

with phase-specific cytotoxicity [40]. Cytarabine is avail-

able as 2 different formulations—a conventional for-

mulation (cytarabine) and a sustained-release or depot

formulation (cytarabine liposome) [40].

Cytarabine

Cytarabine is indicated for the treatment of acute non-

lymphocytic leukemia, acute lymphocytic leukemia, the

blast phase of chronic myelocytic leukemia, and meningeal

leukemia in combination with other chemotherapy agents

[40, 41]. When used for meningeal leukemia, the dose of

cytarabine ranges from 5 to 75 mg/m2 given intrathecally

daily for 4 days or once every 4 days per the product

labeling. Intrathecal cytarabine has also been given as part

of a combination regimen, along with methotrexate and/or

corticosteroids, for prophylaxis and treatment of CNS

malignancies. Various doses of intrathecal cytarabine have

been administered usually dependent upon frequency of

administration and patient age [20, 42, 43]. Most com-

monly no more than 100 mg weekly is administered;

however, high doses (210 mg in 3 doses on alternate days)

have been given in certain situations.

When given intravenously, cytarabine is rapidly metab-

olized by hepatic cytidine deaminase to an inactive metab-

olite [40]. Cytarabine crosses the BBB to achieve detectable

concentrations in the CSF [44]. The elimination half-life of

cytarabine in the CSF is prolonged (up to 6 h) due to low

amounts of cytidine deaminase in the CSF [20, 40].

Cerebrospinal fluid concentrations of cytarabine have

been assessed following intrathecal as well as high-dose

intravenous administration. Following intrathecal adminis-

tration, CSF concentrations of cytarabine following a first

and second 30 mg/m2 dose were 207 and 345 mcM (52 and

86 mcg/mL). Concentrations after a first and second dose of

60 mg/m2 were increased at 397 and 872 mcM (99 and 218

mcg/mL), respectively [45]. High-dose intravenous cytara-

bine (1 or 3 g/m2) has been used to achieve therapeutic

concentrations of cytarabine in the CSF [46, 47]. Slevin and

colleagues evaluated the pharmacokinetics of intravenous

high-dose cytarabine (given over 3 h) in the plasma and CSF

[46]. Following a 1 g/m2 dose, the CSF concentration of

cytarabine was 123 ng/mL, with a CSF: plasma ratio of 2.15.

For a 3 g/m2 dose, the CSF concentration was 257 ng/mL

and the CSF: plasma ratio was 4.5. DeAngelis reported

similar results [48]. Patients were given two 3 g/m2 infusions

of cytarabine separated by 24 h. At 6 h, CSF levels of cyt-

arabine were 1.7–3.9 times that of plasma.

Cytarabine liposome

Cytarabine liposome injection is only indicated for

intrathecal treatment of lymphomatous meningitis [49].


123

The usual dose of cytarabine liposome is 50 mg intrathe-

cally (via lumbar puncture or an intraventricular reservoir)

every 14 days for induction/consolidation therapy (for 6

doses total) and every 28 days for maintenance therapy (for

4 doses total).

Pharmacokinetic studies of cytarabine liposome have

determined the CSF concentrations of free cytarabine. The

peak CSF concentrations of free cytarabine ranged from 30

to 50 mcg/L within 1 h following intrathecal administra-

tion of 50 mg of cytarabine liposome [49]. The half-life

for free cytarabine in the CSF ranged from 6 to 82 h.

Phuphanich and colleagues reported ventricular CSF con-

centrations of free cytarabine of 1.5–116 mcg/mL within

5 h of intraventricular administration (via Ommaya reser-

voir). Lumbar CSF concentrations ranged from 0.1 to 79

mcg/mL within 5 h of lumbar puncture administration [50].

It was also observed that the CSF concentrations of lipo-

some-encapsulated cytarabine were initially higher than

that of free cytarabine following intrathecal administration

(about tenfold). Concentrations declined after several days

to a ratio of 4 and then to 1.2 approximately 14 days after

administration.

Overview of clinical data

The current guidelines from the National Cancer Collabo-

rative Network (NCCN) include intrathecal cytarabine or

cytarabine liposome in the treatment algorithms for lym-

phoblastic lymphoma, lymphomatous meningitis, and/or

leptomeningeal metastases [51]. The liposomal formulation

of cytarabine has the advantage of less frequent dosing,

every 2 weeks versus twice weekly with the conventional

formulation.

Glantz and colleagues compared intrathecal cytarabine

with cytarabine liposome for the treatment of lymphoma-

tous meningitis during an open-label trial [37]. Twenty-

eight patients with cytologically confirmed lymphomatous

meningitis were randomly assigned to treatment with either

cytarabine liposome 50 mg or cytarabine 50 mg for

induction, consolidation, and maintenance therapy. Over-

all, cytarabine liposome was associated with a better

response rate (negative CSF cytology and neurologically

stable; 71 % vs. 15 %). Longer times to neurologic pro-

gression were also observed with the liposomal formulation

as compared with cytarabine (78.5 days vs. 42 days).

Adverse events were more frequent with the liposomal

formulation and included headache, nausea, vomiting,

fever, and confusion. Jaeckle and colleagues reported the

results of cytarabine liposome for the treatment of solid

tumor neoplastic meningitis secondary to breast cancer

[52]. Fifty-six women received cytarabine liposome 50 mg

for induction and consolidation therapy. Of 43 patients

evaluable for a response (defined as negative CSF cytology

and neurologically stable), 12 (28 %) were considered

responders. The median time to neurologic progression was

49 days, and median survival was 88 days. The most fre-

quent adverse events were headache, nausea, vomiting, and

arachnoiditis. Garcia-Marco evaluated the efficacy of cyt-

arabine liposome for the treatment of lymphomatous

meningitis in a retrospective case series of 55 patients [53].

Cytarabine liposome was given as a 50 mg dose once per

cycle for a median of 4 cycles. Twenty-seven patients had a

complete neurologic response and 12 additional patients

had a partial response. Twenty-five patients had a complete

cytologic response. The median time to neurologic pro-

gression was 105 days.

Other intra-CSF chemotherapy agents

In addition to methotrexate and cytarabine, several other

chemotherapy agents have been administered intrathecally.

Data are available for trastuzumab and rituximab, both

monoclonal antibodies, and miscellaneous chemotherapies,

such as busulfan, etoposide, mafosfamide, topotecan,

thiotepa, and gemcitabine. However, published literature

for these agents is primarily in the form of case reports or

case series or early phase trials and provides a limited

strength of evidence. Intrathecal trastuzumab has been used

for the treatment of CNS involvement in patients with

HER2-overexpressing breast cancer with improvement of

stable disease observed in most patients [54–62]. Ritux-

imab has been used for the treatment of relapsed or

refractory CNS lymphomas. Most patients achieved a

partial or complete remission as described in available case

reports [63–74]. For both of these agents, dose and duration

of treatment were variable. The remaining chemotherapy

agents have been used for refractory or metastatic brain

tumors or with meningeal metastases [75–84]. Again,

outcomes and dosing were variable. The use of these agents

is described in detail in the following sections.

Monoclonal antibodies

Trastuzumab

Trastuzumab is a humanized IgG1 kappa monoclonal

antibody indicated as adjuvant treatment of node-positive

or negative, human epidermal growth factor receptor 2

(HER2)-overexpressing breast cancer and for the treatment

of HER2-overexpressing metastatic breast and gastric

cancers [85]. Trastuzumab selectively binds to the extra-

cellular domains of the HER2 protein, resulting in inhibi-

tion of the growth of HER2-overexpressing tumor cells,


123

possibly by affecting growth signaling mechanisms or

through degradation of the HER2 receptor [85, 86]. The

initial dose of trastuzumab is 4 or 8 mg/kg over 90 min

followed by 2 or 6 mg/kg over 30 min intravenously.

Treatment duration is up to 52 weeks or until disease

progression for metastatic breast cancer.

Following intravenous administration, CSF levels of

trastuzumab are low (300-fold lower) compared with

plasma levels, limiting the therapeutic efficacy of trast-

uzumab for CNS malignancies [87]. Stemmler and col-

leagues reported trastuzumab therapy resulted in a serum:

CSF ratio of 420:1 in patients with breast cancer and CNS

metastases following 1 year of therapy. The serum con-

centration of trastuzumab was 52,024 ng/mL compared

with 124 ng/mL in the CNS [88]. For patients who had

received trastuzumab plus radiotherapy, the trastuzumab

serum/CSF ratio decreased to 76:1 (serum and CSF levels

of 20,158 ng/mL and 266 ng/mL). These levels were

measured at a median of 98 days after radiotherapy. A

serum/CSF ratio of 49:1 (17,431 ng/mL vs. 356 ng/mL for

serum and CSF, respectively) was reported at 59 days after

radiotherapy for 2 patients with meningeal carcinomatosis

who had received a median of 44 days of trastuzumab

therapy.

Clinical data on intra-CSF use

Data on the use of intrathecal trastuzumab are limited, with

9 case reports found in the literature. All patients had

metastatic HER2-overexpressing breast cancer with spread

to the CNS (meningeal or brain metastases) [54–62]. Doses

ranged from 12.5 to 25 mg intrathecally, with escalation of

up to 100 mg weekly. All patients had received prior

therapy with various chemotherapy regimens, radiotherapy,

and/or surgery. Most patients had multiple metastases.

Additional intrathecal or systemic therapies were also used

concurrently or following intrathecal trastuzumab. Details

of the case reports are given in Table 2.

Rituximab

Rituximab is a genetically engineered chimeric human/

murine monoclonal IgG kappa antibody indicated for the

treatment of non-Hodgkin’s lymphoma, chronic lympho-

cytic leukemia, and rheumatoid arthritis [89]. Rituximab

selectively binds to the CD20 antigen, expressed on[90 %

of B-cell non-Hodgkin’s lymphomas [89]. The mechanism

of cell death induced by rituximab is unclear but thought to

result from complement-dependent cytotoxicity, comple-

ment-dependent cellular cytotoxicity, antibody-dependent

cytotoxicity, and/or induction of apoptosis [90]. The usual

dose of rituximab for non-Hodgkin’s lymphoma is 375 mg/m2

as an intravenous infusion once weekly for 4 or 8 doses.

For chronic lymphocytic leukemia, the initial dose of rit-

uximab is 375 mg/m2 with subsequent doses of 500 mg/m2

on day 1 of cycles 2–6 [89].

Following repeated intravenous administration, serum

concentrations of rituximab increase proportionally

[90, 91]. In patients with non-Hodgkin’s lymphoma, a

single dose of 375 mg/m2 resulted in a mean peak serum

concentration of 239 mg/L; this increased to 460 mg/L

after the fourth dose. However, CSF concentrations of

rituximab following intravenous dosing are low. Petereit

and colleagues determined the CSF concentrations of rit-

uximab following intravenous administration to patients

with neurologic autoimmune diseases [92]. The highest

CSF concentrations were seen at weeks 3 and 4, reported as

0.170 and 0.201 mg/L, respectively. Rituximab remained

detectable in the CSF for up to 24 weeks. However, the

authors noted that serum concentrations were 1000-fold

higher than CSF concentrations. Harjunpaa and colleagues

reported similar findings. Following intravenous infusions

of rituximab at 375 mg/m2, CSF concentrations were

below 0.55 mcg/mL, compared with a serum concentration

of 400 mcg/mL [93].

Clinical data on intra-CSF use

A number of reports are available describing the use of

intrathecal rituximab for various malignancies. Rubenstein

and colleagues conducted a phase I, open-label trial of

intrathecal rituximab for the treatment of recurrent CNS

lymphoma [94]. Ten patients with relapsed or refractory

CD20-positive CNS lymphoma or intraocular lymphoma

received 1 of 3 dosing regimens: 10 mg, 25 mg, or 50 mg.

Up to 9 injections were given over a 5-week period; once in

week 1 and then twice weekly (days 1 and 4) for 4 weeks.

All injections (5-mL volume, diluted or undiluted) were

given over 1–5 min via an Ommaya reservoir. After the

5-week study period, 3 patients were given intrathecal

rituximab (10 or 25 mg) by lumbar injection as part of the

study protocol. Six patients had cytologic response. The

longest duration of response was 9 months (n = 1). This

same patient also had the longest survival time

(134 weeks). Both the 10 and 25 mg doses were well tol-

erated, with no major toxicities observed. However, the 2

patients who received 50 mg of rituximab experienced

grade 3 infusion related hypertension. The authors also

investigated the pharmacokinetics of rituximab when given

intrathecally. Mean CSF concentrations 1 h postdose via

Ommaya reservoir were 214 and 472 mcg/mL, respec-

tively, for the 10 and 25 mg doses. Estimated average

elimination half-life was 21.9 h for the 10 mg dose, 34.9 h

for 25 mg rituximab, and 13.5 h for 50 mg rituximab.

Serum concentrations of rituximab were \3 % of CSF


123

Table 2 Case reports/case series of intrathecal trastuzumab or rituximab

Reference Indication

(no. patients)

Dose and route Tolerability Outcome

Trastuzumab

Mego et al.

[61]

Breast cancer

with

leptomeningeal

carcinomatosis

(2)

20–100 mg given weekly as

escalating doses with concurrent

cytarabine and methotrexate

Not reported Therapy was well tolerated with

symptom improvement and

reduction in CSF tumor cell

counts. However, both patients

died, one from CNS disease and

the second from liver metastases

Oliveira et al.

[62]

Leptomeningeal

and CNS

metastases (1)

25 mg via lumbar puncture weekly Not reported After 50 doses, functionality was

maintained (e.g., normal gait,

speech, and overall performance)

Ferrario et al.

[54]

Leptomeningeal

metastases (1)

20 mg via Ommaya reservoir with

gradual increase to 30 mg

weekly

After interruption due to toxicity

from concurrent chemotherapy,

trastuzumab was restarted at

40 mg every 3 weeks, with an

increase to 50 mg every 3 weeks

Well tolerated CNS lesions were stable or slightly

decreased after 5 cycles of

trastuzumab and thiotepa.

Additional improvements were

seen (significant reduction in

leptomeningeal lesion size and

resolution of lesions) with

continued therapy

Colozza et al.

[55]

Brain metastases

(1)

12.5 mg via Ommaya ventricular

catheter every 3 weeks

No major side effects Neurologic improvement was seen

after 23 IT injections over

19 months. However, an

increase in lesion size was seen

and new lesions developed and

trastuzumab was stopped;

therapy was changed to lapatinib

and capecitabine

Stemmler

et al. [56]

Meningeal

carcinomatosis

(1)

20 mg via lumbar puncture at

3–6 day intervals

Well tolerated Improvement was seen in walking

and overall general condition.

Remission of meningeal

carcinomatosis was confirmed

with lumbar puncture (absence

of tumor cells). However, the

patient died from liver and lung

metastases

Mir et al. [57] Leptomeningeal

metastases (1)

20 mg 9 1 via lumbar puncture

weekly with weekly dose

escalations (40 mg 9 1, then

100 mg IT 9 4 doses)

Not reported Significant improvement in

neurologic symptoms (resolution

of headaches and ataxia) was

seen after 2 weeks; disease was

stable at 6 weeks. However, the

patient died of progressive brain

metastases

Platini et al.

[58]

Meningeal

carcinomatosis

(1)

20 mg vial lumbar puncture

weekly, increased to 25 mg

Good clinical tolerance Higher functioning and balance

improved despite complications

(extra meningeal infections,

oculomotor paralysis, and upper

temporal quadranopsia), with

disappearance of malignant cells

from CSF. IT trastuzumab was

eventually stopped (after 46

injections over 17 months) and

replaced with oral letrozole

following clinical deterioration

Stemmler

et al. [59]

Meningeal

carcinomatosis

(1)

5 mg via Ommaya reservoir given

at 4–6 days intervals for 4 doses,

with a 5-mg dose escalation to

20 mg. One additional 20 mg

dose was given 3 weeks later

Well tolerated Improvement was seen 2 weeks

after IT trastuzumab and CSF

tumor cell counts remained low

for 11 months. However,

meningeal and cerebral disease

did progress


123

Table 2 continued


(no. patients)


Laufman and

Forsthoefel

[60]

Carcinomatous

meningitis (1)

5 mg via Ommaya reservoir

followed by 10 mg 5 days later,

and 20 mg 17 days after the

initial dose

Not reported No immediate improvement was

seen. The patient was

neurologically stable for 30 days

following the 20 mg trastuzumab

regimen. However, disease

progressed 6 weeks later, with

worsening of symptoms despite

additional IT therapy

Rituximab

Chamberlain

et al. [63]

Recurrent

lymphomatous

meningitis (14)

25 mg twice weekly

intraventricularly for 4 weeks for

induction followed by 25 mg

twice weekly every 4 weeks

(used in combination with

cytarabine liposome)

Arachnoiditis attributed to

cytarabine liposome. A grade 3

allergic reaction occurred with

rituximab after 5 doses

Ten patients had partial remission

for at least 2 months

Hong et al.

[64]

Relapsed primary

CNS lymphoma

(1)

20 mg twice weekly

via 9 2 weeks via Ommaya

reservoir, repeated after partial

remission (total dose 80 mg)

Not reported Patient in remission for 28 months

following high-dose

chemotherapy and autologous

stem cell rescue

Liu et al. [72] CNS relapse of

B-cell

lymphoma (1)

20 mg initially given over 2 min

via lumbar puncture, with

subsequent doses of 30 mg at

2-week intervals for 6 courses

None Complete clearance of CSF

lymphoma cells after the third

infusion, with improvement in

neurologic function. Complete

remission achieved

Villela et al.

[65]

Leptomeningeal

lymphomatosis

due to mantle

cell lymphoma

(1)

25 mg for 5 total doses

(route not specified)

Severe neuropathic pain Patient in remission 25 months

after additional systemic

chemotherapy

Antonini

et al. [66]

Leptomeningeal

lymphoma (1)

Four doses, beginning with 10 mg

(2.5 mg/mL), then 20 mg,

30 mg, and 40 mg given via

lumbar puncture as a 2-minute

infusion

Headache, cramps, and severe

back pain after the 40 mg

dose, which were relieved by

antihistamines,

dexamethasone, and morphine

Complete clinical remission,

following additional systemic

chemotherapy

Billio et al.

[67]

Relapsed

meningeal

Burkitt’s

leukemia/

lymphoma (1)

Four courses of 25 mg, given via

Ommaya reservoir

None Complete remission after

35 months, following additional

intrathecal and systemic

chemotherapy

Takami et al.

[68]

Primary CNS

lymphoma (1)

Three doses, 10 mg/9 mL, 40 mg/

12 mL, and 50 mg/13 mL

(initial concentration of 10 mg/

mL diluted with 8 mL of

autologous serum) on days 1, 3,

and 6, via Ommaya reservoir

infused over 5 min. An equal

volume of CSF fluid was

removed prior to each infusion

None Disease initially progressed, with a

partial remission 8 weeks after

rituximab. However, the

patient’s clinical condition

worsened with eventual disease

progression and death

Schulz et al.

[69]

Relapsed CNS

lymphoma (6)

Variable dosing—10–40 mg in

1–4 mL volume over 2 min via

an Ommaya reservoir or

intrathecally given weekly for up

to 5 weeks. An equal volume of

CSF fluid was removed prior to

each infusion

Nausea, chills, hypotension

(NCI Grade 1), severe pain

attack, paraparesis (NCI Grade

3)

Four patients had total clearing or

remission of meningeal/

leptomeningeal involvement.

Parenchymal progress or minor

response occurred in 3 patients.

Maximum CSF concentration of

rituximab was 35.4 mcg/ml at

24 h after 25–30 mg dosing


123

concentrations. Rituximab concentrations were also mea-

sured in the Ommaya reservoir 90 min after lumbar

puncture administration for the determination of distribu-

tion into the ventricular space. These values were

approximately 7, 13, and 13 mcg/mL for the 10, 25, and

50 mg doses, respectively. These levels were substantially

lower than those reported with intraventricular adminis-

tration. A published comment on this study suggested that

the finding supports intraventricular but not intralumbar

administration [95].

Jaime-Perez reported the results of an open-label trial

enrolling 7 pediatric and young adult patients with

CNS-relapsed, CD20-positive, B-cell acute lymphoblastic

leukemia refractory to triple intrathecal therapy (metho-

trexate, cytarabine, and hydrocortisone; median of 23

intrathecal injections) [96]. Rituximab 10 mg in 6 mL of

normal saline was given intrathecally every week for

4 weeks. 6-mercaptopurine and methotrexate were also

administered. Triple intrathecal therapy was resumed

7 days after the last rituximab dose. At 24 months or

greater follow-up, 5 of the 7 patients were in complete

remission. Two patients died following bone marrow and/

or testicular relapse.

In addition, 10 case reports described intrathecal ritux-

imab administration for the treatment of primary CNS

lymphomas, either refractory or relapsed [63–72]. Ritux-

imab dosing was variable, ranging from 10 to 50 mg.

Frequency and route of administration also varied, with

rituximab given weekly or twice weekly, either via lumbar

puncture or an Ommaya reservoir. Most patients had

received extensive chemotherapy (systemic or intrathecal)

prior to and after completion of intrathecal rituximab. Two

case reports described use of intrathecal rituximab in

pediatric patients [73, 74]. Akyuz reported successful use

of rituximab in a 14-year-old patient with refractory pri-

mary CNS lymphoma [73]. The dose ranged from 10 to

35 mg given via an Ommaya reservoir. Fever and disori-

entation were seen with higher doses (25 and 35 mg,

respectively). The patient experienced a complete response

and was stable 7 months after treatment. In the second case

report, a 10-year-old patient received intrathecal rituximab

for CNS lymphoproliferative disease following kidney

transplant [74]. After failure of intravenous rituximab

(375 mg/m2), intrathecal administration using an Ommaya

reservoir was performed. Rituximab was given as 40 mg

on days 1, 8, and 15 of a 21-day cycle in combination with

other systemic and intrathecal therapies. Four cycles were

given with resulting tumor size stabilization and remission

of neurologic symptoms. Tingling of the extremities and a

transient upward gaze of the eyes occurred during ritux-

imab administration. Details of the additional case reports

in adults are given in Table 2.

Miscellaneous agents

Busulfan

Busulfan is an alkylating agent approved for use in com-

bination with cyclophosphamide as a conditioning regimen

prior to allogeneic hematopoietic progenitor cell trans-

plantation for chronic myelogenous leukemia (CML)

(injectable formulation) and for the palliative treatment of

CML (oral formulation) [97]. Limited phase I studies have

been completed evaluating the efficacy and safety of a

novel formulation of busulfan (Spartaject Busulfan) as an

intrathecal treatment for patients with neoplastic meningitis

[75, 98]. Spartaject Busulfan is a water soluble micro-

crystalline formulation that allows for direct medication

delivery into the CSF.

Penne and colleagues enrolled 32 patients in a study in

order to assess the maximum tolerated dose, safety profile,

and pharmacokinetics of Spartaject Busulfan [98]. Patients

received busulfan 2.5 mg initially with dose escalation (via

a Modified Fibonacci series and cohort size of 3 patients)

up to 21.25 mg at the time of study publication. Drug

administration occurred twice weekly for 2 weeks either

intraventricularly or via lumbar puncture. Of the 32

enrolled patients, 4 were non-evaluable. Twelve patients

had stable disease for at least 4 treatments, 11 experienced

progressive disease, and 5 patients demonstrated a partial

response with 5–10 treatments. Significant (Grade 3 or 4)

toxicity was minimal. Two patients each experienced

Table 2 continued


(no. patients)


Pels et al.

[71]

Relapsed primary

CNS lymphoma

(1)

25 mg twice weekly via Ommaya

reservoir (total dose 200 mg)

None Some clinical improvement with

partial remission of parenchymal

tumor after 4 weeks

Pels et al.

[70]

Refractory

primary CNS

lymphoma (1)

Four doses given—10 mg/mL on

day 16, 40 mg/mL on day 17,

and 25 mg/2.5 mL on days 24

and 25 via Ommaya reservoir

WHO Grade 3 nausea, chills,

and hypotension after 40 mg

dose

Clinical improvement and clearing

of lymphoma cells from CNS.

Tumor size was not affected and

progression occurred


123

Grade 3 seizures (after resection of intracerebral metasta-

ses), development of reservoir infections, and light-

headedness/faintness. One patient had Grade 3 headache/

nausea related to cerebral edema. Grade 4 effects included

hematologic toxicities (n = 2) and diverticulitis (n = 1).

Five patients underwent pharmacokinetic analyses, with

busulfan therapy resulting in continuously high CSF levels

for several hours following administration and rapid

clearance of the drug from the blood thereby limiting

hematologic toxicity.

The Pediatric Brain Tumor Consortium study evaluated

the use of intrathecal Spartaject Busulfan in 28 pediatric

patients with neoplastic meningitis [75]. The usual starting

dose of busulfan was 5 mg for children C3 years of age;

80 % of this starting dose was given to children between 2

to 3 years of age due to their lower CSF volume. The dose

of busulfan could be escalated up to 21 mg. Busulfan was

given twice weekly for 2 weeks followed by an assessment

of clinical response and adverse effects. Children with

stable disease or an objective response continued to receive

therapy (intrathecal busulfan and systemic chemotherapy)

at regular intervals. Estimation of the maximum tolerated

busulfan dose and evaluation of dose-limiting toxicities

were performed in 23 patients (median age: 8.8 years). The

recommended dose of Spartaject Busulfan for subsequent

studies was determined to be 13 mg. The 7 patients treated

with this dose did not experience any significant medica-

tion-related toxicity. The following dose-limiting toxicities

(Grade 3) were noted in 3 separate patients: emesis (5 mg

dose), headache, and arachnoiditis (both occurring with a

17 mg dose). Nine patients had stable disease and 14

experienced disease progression after the initial treatment

course. Pharmacokinetic data from 6 patients found ven-

tricular busulfan concentrations via an Ommaya reservoir

to be quite high ([100 lg/mL); however, levels were much

lower following lumbar administration. In addition,

detectable plasma levels of busulfan were seen in this study

with maximum concentrations (0.15–0.38 lg/mL) noted

30 min to 2 h following drug administration.

Etoposide

Etoposide is indicated for use in refractory testicular

tumors and small cell lung cancer, but has been adminis-

tered in a variety of malignancies [99, 100]. This semi-

synthetic derivative of podophyllotoxin produces a

cytotoxic effect through inhibition of DNA topoisomerase

II, and by metabolic activation in oxidation–reduction

reactions producing derivatives that bind directly to cel-

lular DNA [99]. There are currently limited data on CNS

administration of etoposide. In 1992, van der Gaast and

colleagues reported on the successful intrathecal adminis-

tration of etoposide in 2 patients with malignant meningitis

resulting from small cell lung cancer and chronic myelo-

cytic leukemia, respectively [76]. Both patients received

etoposide 0.5 mg diluted in 2 mL saline intraventricularly

once daily for 5 days followed 3 weeks later by a second

course where the same dose was given twice daily for

another 5 days. Both patients experienced an absence of

malignant cells from the CSF initially, with no treatment-

related adverse effects. Cerebrospinal fluid etoposide levels

up to 5.2 lg/mL were observed.

Following these initial cases, 14 children and adoles-

cents (2.1–33.2 years of age) with relapsed metastatic brain

tumors were involved in a pilot study investigating the

feasibility of intraventricular administration of etoposide

[78]. Etoposide 0.5 mg was injected over 2 min daily for

5 days via an Ommaya or Rickham reservoir, with repeated

courses administered every 2–5 weeks over 10–11 months

of total therapy. A total of 59 courses of etoposide were

given. Although the clinical efficacy of intraventricular

etoposide could not be assessed independently due to

concurrent chemotherapy and irradiation, 5 patients expe-

rienced improvement in neurologic or pain symptoms, 6

had no changes, and 3 demonstrated symptomatic pro-

gression. Only 4 patients underwent repeated ventricular

and lumbar CSF samples to examine cytology. All 4

experienced initial clearance of malignant cells after 1–5

courses of etoposide therapy. Overall, concurrent systemic

chemotherapy and intraventricular etoposide resulted in the

following disease responses: complete (n = 2), partial

(n = 7), stable disease (n = 1), mixed (n = 2), and pro-

gressive disease (n = 2). Intraventricular etoposide was

well tolerated with mild transient headache and bacterial

meningitis observed; both effects were successfully treated.

Mafosfamide

Mafosfamide is a chemically stable 4-thioethane sulfonic

acid salt of 4-hydroxycyclophosphamide that was desig-

nated by the FDA as an orphan drug for the treatment of

neoplastic meningitis in 2003 [101, 102]. Since mafosfa-

mide does not require hepatic activation to express an

antitumor effect, unlike cyclophosphamide, this agent may

be potentially useful as an intrathecal chemotherapy option

[103]. The cytotoxic activity of mafosfamide has been

demonstrated to be similar to activated cyclophosphamide,

4-hydroxy-peroxycyclophospamide in an in vitro study

[104]. Clinical data on mafosfamide administration into the

CNS are limited; however, a few case series and a single

phase I trial have been published [79, 80, 101]. In 1998,

Slavc and colleagues published a case series evaluating the

administration of intrathecal mafosfamide to 16 pediatric

patients with brain tumors and meningeal dissemination

[79]. Enrolled patients had a median age of 12 years (range

2–19 years). The most common diagnosis among the


123

enrolled children was disseminated medulloblastoma

(n = 7). Mafosfamide was administered intraventricularly

via an indwelling Rickham or Ommaya reservoir with

some patients also receiving mafosfamide via the intra-

lumbar route. Thirteen of the 16 total patients eventually

received mafosfamide at a dose of 20 mg once or twice

weekly until achievement of remission. This was followed

by weekly administration as consolidation and mainte-

nance therapy thereafter every 3–4 weeks. All patients

received concurrent systemic chemotherapy involving

ifosfamide and cisplatin. Of the 9 patients who were

evaluable for response by CSF cytology, 8 had a complete

response (defined as complete clearing of malignant cells

for 3 consecutive weeks) after mafosfamide induction

therapy. At the time of publication, 7 patients remained in

complete remission, 4 in partial remission, and 2 had stable

disease. The remaining 3 patients died due to tumor pro-

gression. For the surviving patients, the median time of

follow-up since initial diagnosis or last relapse was

21 months. Therapy-related adverse effects were minor but

frequent with transient headache, nausea, and vomiting

occurring in approximately 66 % of patients. These

effects occurred during or immediately after intraven-

tricular administration. Sleepiness was also observed fol-

lowing administration, primarily in young children.

Removing an equivalent CSF quantity before adminis-

tration and giving mafosfamide over a longer time period

(i.e., [5 min) may reduce the frequency of these effects.

The same investigators published another case series in

2003 involving 26 pediatric patients (including follow-up

of patients from the 1998 case series) with disseminated

malignant brain tumors treated with long-term intraven-

tricular mafosamide [80]. Based on MRI imaging and

neurologic evaluations, patients did not experience any

chronic mafosfamide-related toxicities. Since all patients

received some form of concurrent systemic chemotherapy,

the efficacy of continued mafosfamide therapy was diffi-

cult to assess.

In a phase I study of mafosfamide, 33 patients (C3 years

of age) with meningeal spread of leukemia, lymphoma, or a

solid tumor refractory to conventional therapy were

enrolled [101]. Five different dosages of intrathecal

mafosfamide were administered; starting at a dose of 1 mg

with subsequent increases to 2, 3.5, 5, and 6.5 mg. In

general, mafosfamide administration was well tolerated;

however, as the drug dose was elevated, a corresponding

increase in headaches (often accompanied by flushing or

neck pain) was reported during or immediately after infu-

sion completion. Overall, 29 patients were assessed with

regard to response; 7 had a partial response, 6 were found

to have stable disease, and 16 experienced progressive

disease. Of the doses administered, the investigators con-

cluded that 5 mg, given at a constant infusion rate over

20 min, was the recommended dose to be used in phase II

studies.

Topotecan

Topotecan is a camptothecin analog that has been used for

the treatment of neoplastic meningitis in association with

solid tumors and hematologic malignancies [21]. The

pharmacokinetics and efficacy of intrathecal topotecan

were investigated in a phase I trial enrolling 23 patients

(mean 12 years; range 3–63 years) with neoplastic men-

ingitis. A dose escalation—0.025 mg twice weekly, with

the dose doubled up to 0.2 mg based on toxicity—was used

for the first 3 patients. The remaining patients were treated

with fixed doses of 0.2, 0.4, or 0.7 mg. Following a 0.4 mg

intraventricular dose given via an Ommaya reservoir, the

mean ventricular CSF concentration was 28 (±11) lmol/L.

Elimination of the drug from the CSF was rapid, with a

mean half-life of 157 (±54) min [103]. Six of the 23

patients benefited from treatment, either as reductions in

CSF cell counts or stable disease. Arachnoiditis was the

major toxicity seen, manifesting with fever, nausea, vom-

iting, headache, and back pain.

On the basis of the above results, a phase II trial was

conducted using topotecan at a dose of 0.4 mg twice

weekly via an implanted ventricular access device [81].

Sixty-two patients (median 62 years; range, 5–83 years)

with meningeal malignancies were included. Topotecan

was given for 6 weeks and continued weekly for another

6 weeks as consolidation therapy if there was no evidence

of progressive meningeal disease. Topotecan was then

given twice monthly for 4 months and then monthly as

maintenance therapy until disease progression or toxicity.

After the initial 6 weeks of therapy, 13 patients had

clearing of the CSF. On the basis of clinical response, 10

patients were considered improved and 18 were stable. The

median time to progression was 7 weeks, and the overall

survival was 15 weeks. Chemical meningitis and CNS

symptoms were the most commonly reported adverse

events, occurring in 32 and 18 % of patients, respectively.

Thiotepa

Thiotepa is an aziridine that has been administered intra-

thecally for the treatment of CNS malignancies associated

with solid tumors as well as primary brain tumors and

meningeal leukemias [21]. However, the need for intra-

thecal administration has been questioned based on the

high lipid solubility of the drug [82]. In a phase I trial,

Heideman reported CSF/plasma ratios of thiotepa and its

major active metabolite to be 1.02 and 0.95, respectively,

following intravenous administration [105]. Intrathecal use

of thiotepa has been described in 2 retrospective studies,


123

both with pediatric patients with meningeal metastases [82,

83]. The dose of thiotepa ranged from 5 to 11.5 mg/m2

given weekly via the lumbar route or an implanted ven-

tricular reservoir. In one study, responders had a median

survival time of 15.5 months compared with 10 months

among non-responders [83]. As reported in the second trial,

the overall survival rate was 26.7 %, with survival times

ranging from approximately 2 months to nearly 14 years.

Gemcitabine

Bernardi and colleagues published a phase I study

involving intrathecal gemcitabine administration to 10

patients (C3 years of age) with neoplastic meningitis sec-

ondary to an underlying leukemia, lymphoma, or solid

tumor in 2008 [84]. Gemcitabine was given via Ommaya

reservoir or lumbar puncture at 3 different dosages: 5 mg

weekly, 5 mg twice weekly, and 10 mg twice weekly

through a standard dose escalation study design. Three

patients exhibited a stable disease response, with no com-

plete responses observed. In addition, significant neuro-

toxicity including myelitis and somnolence were seen. Due

to these significant neurotoxicities, intrathecal gemcitabine

administration is no longer being developed as a thera-

peutic option.

Summary

For LMC from solid tumors, intrathecal sustained-release

cytarabine, as well as a combination of intrathecal

methotrexate with cytarabine plus hydrocortisone when

compared with intrathecal methotrexate alone, is associ-

ated with significantly improved median time to neurologic

progression and significantly improved median survival,

respectively. For LMC with breast cancer, liposomal cyt-

arabine demonstrated activity that is comparable to results

reported with conventional intrathecal agents; requiring

only one-fourth as many intrathecal injections compared

with conventional therapy [52]. Data from case reports

suggest that intraventricular and intrathecal administration

of trastuzumab at variable doses for HER-2 positive tumors

is well tolerated and provides neurologic improvement,

reduction in CSF cell count and stable or slightly decreased

lesions. In children with LMC from brain tumors, Sparta-

ject Busulfan is well tolerated at a dose of 13 mg.

For LMC from hematologic malignancies, such as

lymphomatous meningitis, liposomal cytarabine needs less

frequent dosing and has better clinical outcomes with

improved response rate and longer time to neurologic

progression as compared to free cytarabine. Data from case

reports suggests that rituximab helps achieve partial to

complete remission, improvement in neurological function,

and clearance of CSF lymphocytic cells.

Treatment of LMC fails due to physiologic barriers,

marginally effective drugs, treatment-resistant histologies,

poor functional status at time of diagnosis, and progression

of systemic disease [106]. Efficacy of most currently

available intra-CSF agents is compromised by a short half-

life within the CSF and a cell-cycle phase-specific mech-

anism of action resulting in inadequate drug distribution

[17]. Newer drugs with improved circulation time may

serve this purpose.

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