Comparison of Intrathecal Chemotherapy for Leptomeningeal Carcinomatosis of a Solid Tumor: Methotrexate Alone Versus Methotrexate in Combination with Cytosine Arabinoside and Hydrocortisone

Abstract

To compare the efficacy of intrathecal methotrexate single therapy with three-drug combination therapy in patients with leptomeningeal carcinomatosis.
Fifty-five patients who had pathologically proven leptomeningeal carcinomatosis of a solid tumor were evaluated in terms of pathological response. Group M (n = 29) received methotrexate 15 mg and group MHA (n = 26) received methotrexate 15 mg, hydrocortisone 15 mg/m(2) and ara-C 30 mg/m(2) twice a week intrathecally until a cytological response was obtained.
Primary sites of the tumor were the lung (n = 33), breast (n = 13) and stomach (n = 5). The pathology of 45 patients was adenocarcinoma. The cytological response rate to intrathecal chemotherapy was significantly higher in the MHA group than in the M group (38.5 vs 13.8%, P = 0.036). The median survival was 18.6 weeks in the MHA arm and 10.4 weeks in the M arm (P = 0.029).
Combination intrathecal chemotherapy with methotrexate, cytosine arabinoside and hydrocortisone showed more favorable effects than methotrexate single therapy for leptomeningeal carcinomatosis in solid tumors.

Full text

Jpn J Clin Oncol 2003;33(12)608–612
© 2003 Foundation for Promotion of Cancer Research
Original Articles
Comparison of Intrathecal Chemotherapy for Leptomeningeal
Carcinomatosis of a Solid Tumor: Methotrexate Alone Versus
Methotrexate in Combination with Cytosine Arabinoside and
Hydrocortisone
Dae-Young Kim, Keun-Wook Lee, Tak Yun, Sook Ryun Park, Joo Young Jung, Dong-Wan Kim, Tae-You Kim, Dae
Seog Heo, Yung-Jue Bang and Noe Kyeong Kim
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
For reprints and all correspondence: Dae Seog Heo, Department of Internal
Medicine, Seoul National University Hospital, Cancer Research Institute,
Seoul National University College of Medicine, 28 Yongon-dong, Chongro-
gu, Seoul, Korea. E-mail: heo1013@plaza.snu.ac.kr
Received September 29, 2003; accepted November 11, 2003
Objective: To compare the efficacy of intrathecal methotrexate single therapy with three-drug
combination therapy in patients with leptomeningeal carcinomatosis.
Methods: Fifty-five patients who had pathologically proven leptomeningeal carcinomatosis of
a solid tumor were evaluated in terms of pathological response. Group M (
n
= 29) received
methotrexate
15
mg
and
group
MHA
(
n
=
26)
received
methotrexate
15
mg,
hydrocortisone
15 mg/m
2
and ara-C 30 mg/m
2
twice a week intrathecally until a cytological response was
obtained.
Results: Primary sites of the tumor were the lung (
n
= 33), breast (
n
= 13) and stomach (
n
=
5). The pathology of 45 patients was adenocarcinoma. The cytological response rate to intra-
thecal chemotherapy was significantly higher in the MHA group than in the M group (38.5 vs
13.8%,
P
= 0.036). The median survival was 18.6 weeks in the MHA arm and 10.4 weeks in the
M arm (
P
= 0.029).
Conclusion:
Combination
intrathecal
chemotherapy
with
methotrexate,
cytosine
arabino-
side and hydrocortisone showed more favorable effects than methotrexate single therapy for
leptomeningeal carcinomatosis in solid tumors.
Key words: meningeal neoplasms – spinal injections– methotrexate – cytarabine
INTRODUCTION
Leptomeningeal
carcinomatosis
(LMC)
from
solid
tumors
is
a clinically important neurological complication of systemic
cancer (1), the presence of which usually indicates a grave
prognosis of 4–6 month median survival irrespective of inten-
sive treatments. Since the first case was described in 1870 by
Eberth (2), much improvement in the systemic chemotherapy
of neoplastic diseases has resulted in an increased incidence of
LMC in many types of solid tumors (3).
A diagnosis of LMC can be made with positive cytology in
the cerebrospinal fluid (CSF) or by typical findings on neuro-
imaging studies or by clinical criteria alone, in a patient with
known cancer and neurological dysfunctions at multiple levels
of the neuraxis (1). As to the treatment of LMC, it is generally
accepted that the standard therapy involves introducing
chemotherapeutic agents directly into the CSF (i.e. intrathecal
or intraventricular chemotherapy) in combination with radio-
therapy
directed
to
the
areas
of
major
clinical
involvement
(3). Although there is some debate about the efficacy from the
perspective of survival benefit (3,4), many reports have agreed
upon the beneficial role of intrathecal chemotherapy on the
survival of patients with LMC.
Methotrexate remains the most frequently used drug for
intrathecal administration, despite limited success and serious
toxicities (5). Other drugs used are cytosine arabinoside (ara-
C), thiotepa and L-asparaginase, which have been tried in hu-
mans, and the use of which in solid tumor LMC has been
extrapolated from data on the treatment of leukemic meningitis
(6). The efficacy of single-regimen intrathecal chemotherapy
with methotrexate for solid tumor LMC is believed to be un-
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Jpn J Clin Oncol 2003;33(12) 609
satisfactory (1) and many efforts have been made to improve
the response rate and survival by combining methotrexate with
other agents, such as ara-C and thiotepa.
Several reports have described the use of these drugs in
sequence or in combination with methotrexate and many failed
to find any superiority of combination therapy over single
therapy (3,4,7,8). However, our experience of systemic chemo-
therapy suggests that chemotherapy based on a combination
regimen produces improved treatment results. Also our clinical
experience was different from those which others had previ-
ously reported about the efficacy of combination intrathecal
chemotherapy. We hypothesized that the difference was caused
by the different patient populations and the different methods
of efficacy evaluation. Therefore, this study was performed to
compare retrospectively the efficacies of intrathecal metho-
trexate single therapy (M) with a three-drug combination
therapy (methotrexate, hydrocortisone and ara-C; MHA),
using response criteria based on pathological conversion in
patients with solid tumors LMC.
PATIENTS AND METHODS
PATIENT ELIGIBILITY
Fifty-five patients with pathologically proven solid tumor
LMC (with a positive cytology in the CSF) which was diag-
nosed consecutively in our center between January 1995 and
July 2002 were enrolled in this study. All patients had histolog-
ically confirmed malignancy and were not excluded because of
the performance status, tumor types or the stage of systemic
disease. Patients with acute or chronic leukemia or lymphoid
malignancy were excluded.
TREATMENT SCHEME
All patients underwent intrathecal chemotherapy after con-
firmation of a positive CSF cytology. All chemotherapeutic
agents were diluted in sterile normal saline and administered
intrathecally by repeated lumbar puncture. No patients under-
went Ommaya reservoir placement. The treatment regimen
was determined for each patient at the discretion of the attend-
ing physician and they followed a common assignment algo-
rithm. A group of patients (n = 29) received methotrexate 15
mg (M) and the others (n = 26) received methotrexate 15 mg,
hydrocortisone 15 mg/m
2
and ara-C 30 mg/m
2
(MHA) concur-
rently. Treatment sessions were repeated twice a week and
patients were assessed for response by complete clearing of all
malignant cells from lumbar CSF. The responders, whose CSF
showed no malignant cells or no atypical cells, received a
weekly maintenance therapy with the same regimen as the pre-
vious one while response persisted. If progression occurred on
the M arm, ara-C and hydrocortisone were added. Patients
were taken off intrathecal chemotherapy if progression
appeared on the combined MHA arm or performance status
worsened.
Folic acid was administered at the initiation of the therapy or
after
the
development
of
myelosuppression
at
the
discretion
of the attending physician. Cranial and/or spinal irradiation
therapy
(RT)
was
directed
towards
the
symptomatic
sites
in
the neuraxis and towards all bulky disease evident on neuro-
imaging studies. RT was not assigned randomly; the decision
to use RT was made principally if symptomatic areas or mass
lesions were present on neuroimaging studies.
CRITERIA FOR ASSESSMENT OF EFFICACY AND ADVERSE
EFFECT S
CSF was obtained and examined at each cycle. Serial exami-
nations, including cytology, complete cell count, differential
count, glucose and protein, were performed. Neurological sta-
tus was assessed at the initiation of therapy and was reassessed
before each course. Assessment of neurological status was
based on the patient’s subjective evaluation of neurological sta-
tus improvement and the opinion of observer physicians who
were not the attending physician. A neurological improvement
was
defined
as
a
decrease
in
intensity
or
a
disappearance
of
the initial neurological symptoms and signs and a neurological
response was defined as the presence of neurological stabiliza-
tion
or
improvement
persisting
for
at
least
4
weeks.
Criteria
for
a
cytological
response
included
the
complete
clearing
of
Tab le 1. Characteristics of the patient groups
*Cranial and/or spinal radiation therapy.
†
Systemic chemotherapy.
Tot a l M MH A P value
Patient No.552926
Gender
Male 21 11 10 0.968
Female 34 18 16
Median age (range) 55 (17–71) 53 (29–71) 57.5 (17–69) 0.999
Primary site
Lung 33 16 17 0.338
Breast 13 7 6
Stomach532
Others431
Histology
Adenocarcinoma 45 24 21 0.915
Small cell 5 1 4
Others541
Bulky CNS disease 35 18 17 0.799
Performance status
(ECOG)
Grade 1–2351817 0.799
Grade 3–420119
Concurrent RT*271314 0.504
Concurrent sCTX
†
3 2 1 1.000
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610 Combined vs single intrathecal CTX
all malignant cells from lumbar CSF in at least two serial
examinations and the presence and continuation of neurologi-
cal response. To evaluate adverse effects, complete blood cell
count and biochemical profiles were monitored at least weekly,
if the patient’s performance status permitted.
STATISTICAL METHODS
Comparisons of categorical variables between the two groups
with respect to the response data were made using the chi-
square test and Fisher’s exact test. Survival curves were
generated by the Kaplan–Meier method. Comparisons were
deemed statistically significant when the two-tailed P value
was <0.05.
RESULTS
Twenty-nine patients received M and 26 patients received
MHA. The characteristics of all patients and of the patient
groups are listed in Table 1. The primary tumors of 55 patients
were of the lung (60.0%), breast (23.6%) and stomach (9.1%).
Of the other patients, two had rhabdomyosarcoma, and in the
two remaining patients the primary site could not be identified.
The median number of cycles of intrathecal chemotherapy in
the 55 patients was seven (range: 2–24) – eight in the MHA
arm and six in the M arm. The median number of treatments to
cytological response in cytological responders was 3.5 (range:
1–9) and there was no statistically significant difference
between the two arms (M vs MHA: 4.5 vs 3.5, P = 0.713).
Cytological response was observed in 14 patients (25.5% of all
patients) and neurological response in 36 patients (65.5%). The
cytological response rate of the MHA arm was higher than that
of the M arm and this was statistically significant (38.5 vs
13.8%, P = 0.036). Even though the five patients with small
cell lung carcinoma were excluded in the analysis, the response
rate of the MHA arm exceeded that of the M arm (27.3 vs
14.3%, P = 0.302), but the difference was not statistically sig-
nificant. The neurological response rate was not different sig-
nificantly between the two treatment arms (M vs MHA: 58.6 vs
73.1%, P = 0.260).
When patients were categorized in terms of primary tumor
and histology, patients with small cell lung cancer fared best
(4/5 patients, 80.0%), followed by breast cancer (5/13 patients,
38.5%), stomach cancer (1/5 patients, 20.0%) and adenocarci-
noma of lung (4/25 patients, 16.0%) in the cytological response
rate.
Cytological response rate among patients who did not
received concurrent CNS irradiation was 32.1%, which was
higher than those that received CNS irradiation (18.5%), but
the difference was not significant (P = 0.246). In patients who
did not receive CNS irradiation, the difference between the two
treatment arms (M and MHA) became more prominent and
statistically significant (12.5 vs 58.3%, P = 0.017) than for
those who received CNS irradiation (15.4 vs 21.4%, P =
0.686). The presence of brain and/or spinal parenchymal
metastasis did not affect the response rate significantly. (31.4
vs 15.0%, P = 0.178).
In terms of the neurological response rate, differences in the
primary tumor site and the presence of brain and/or spinal
parenchymal metastasis did not cause a significant difference,
except that the neurological response rate was higher (81.5%)
among patients who received concurrent cranial and/or spinal
radiation therapy than in those (50.0%) who did not (P =
0.014). The duration of neurological response was 5.1 weeks in
patients who responded neurologically. We could not obtain
the result for the cytological response duration, because for
many patients who showed cytological responses further
follow-up CSF examinations were not performed to evaluate
the cytological response duration, mainly owing to loss to
follow-up.
The treatment-related toxicity was tolerable in both treat-
ment arms. No hematological and non-hematological toxicities
over grade 3 (WHO criteria) were observed. In the M arm, two
patients experienced an episode of grade 1–2 leukopenia and
one patient grade 1 neurotoxicity. In the MHA arm, three
Figure 1. Survival curves for the two treatment arms. Solid line, MHA; broken
line, M; P = 0.029, Breslow.
Figure 2. Survival curves for cytological responder vs non-responder. Solid
line, responder; broken line, non-responder; P = 0.631, log rank.
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Jpn J Clin Oncol 2003;33(12) 611
patients experienced grade 1–2 leukopenia and one case of
elevated hepatic enzyme was reported (grade 1).
Fig. 1 shows the Kaplan–Meyer survival curves of the two
treatment arms. The median survival of all 55 patients was 11.9
weeks (range: 2.7–28.7 weeks) and median survival was longer
in the MHA arm than in the M arm (18.6 vs 10.4 weeks, P =
0.029). Survival was longer in the cytological responders than
in the non-responders (22.1 vs 11.6 weeks), but this was not
statistically significant (Fig. 2). In terms of the subgroups
classified by histology and primary tumor type, patients with
adenocarcinoma
of
the
lung
in
the
MHA
arm
showed
a
sur-
vival advantage over those in the M arm, which was statistical-
ly significant (23.9 vs 10.4 weeks, P = 0.038). In breast cancer
patients, the survival predominance of the MHA arm over the
M arm was marked, although it was not statistically significant
(23.7 vs 10.1 weeks, P = 0.445). Patients with concurrent RT
showed an 8-week survival predominance over patients with
no RT, although it was not significant statistically (18.6 vs 10.9
weeks, P = 0.470).
Among 41 patients who expired and whose causes of deaths
were identifiable, 38 patients (93%) died of the progression of
CNS lesion. The proportions of patients between the two arms
were not different (M vs MHA: 92 vs 94%).
DISCUSSION
The treatment results for LMC in solid tumors have not been
satisfactory with the current treatment modalities. Many efforts
have been made to increase the response rate and to prolong
survival with durable remission, for example, by the placement
of an Ommaya reservoir (3), by intravenous methotrexate (9)
and by concurrent or sequential radiation therapy and systemic
chemotherapy. Trials of combination regimens of intrathecal
chemotherapy with methotrexate and other drugs, such as ara-
C and thiotepa, have also been conducted.
In our study, the cytological response rate and overall sur-
vival were higher in the combined (MHA) treatment arm than
in the single (M) arm in patients of LMC without symptomatic
areas or mass lesions on neuroimaging studies. The difference
in survival could be mainly due to the difference in the
numbers of cytological responders among those who did not
receive irradiation (M vs MHA: 2/16 vs 7/12). There was no
difference in the numbers of responders in patients irradiated
(M vs MHA: 2/13 vs 3/14). Despite the limitation of a retro-
spective study, this result is worthy of consideration. The addi-
tion of ara-C to a methotrexate-based regimen has shown the
possibility of improving the efficacy of intrathecal chemo-
therapy for LMC in solid tumors, especially in LMC patients
without symptomatic areas or mass lesions on neuroimaging
studies. Although the cytological response rate to the com-
bination therapy is encouraging, the superiority should be
suggested prudently when the neurological response rate and
the survival duration were not improved in the responders.
Previous attempts to combine ara-C with methotrexate in
intrathecal
chemotherapy
have
failed
to
prove
the
benefit
of
the regimen. Giannone et al. (3) reported the treatment results
for
22
patients
with
meningeal
neoplasm
of
breast
cancer,
lung cancer and malignant glioma. The simultaneous triple-
drug intraventricular chemotherapy consisting of methotrexate,
cytosine arabinoside and thiotepa caused unacceptable myelo-
suppression without increasing the response rate, response
duration or survival, when compared with single-agent meth-
otrexate and radiotherapy. Hitchins et al. (4) reported that the
response to methotrexate alone was superior to that to com-
bined methotrexate and ara-C, but not significantly so (61 vs
45%, P > 0.10) in a prospective randomized study of 44
patients mainly composed of small cell carcinoma and breast
carcinoma.
Hitchins et al.’s prospective randomized trial (4) and Wasser-
strom et al.’s analysis of 90 patients (1) included some patients
who were clinically suspected of having LMC based on the
abnormalities of neurological findings and imaging studies
without pathological confirmation. In Hitchins et al.’s trial, the
CSF cytology of 11 (25%) patients was negative. In our study,
we confined the inclusion criteria to histologically confirmed
LMC and the definition of the response was based on the
pathological change, namely the clearance of malignant cells
from
the
CSF.
The
differences
in
the
eligibility
criteria
and
the definition of response might have led to the different
results. When a response was merely judged by the neurologi-
cal response as in the previous studies, the two arms in our
study showed no difference in the response rate (M vs MHA:
58.6 vs 73.1%, P = 0.260), which is consistent with the pre-
vious studies.
The histological composition of patients in our study was
different from that in the previous ones. In Grossman and
Krabak’s randomized trial (7), 10 patients (19%) with lym-
phoma were included, which were more responsive to chemo-
therapy than other types of solid tumor. Hitchins et al.’s trial
included 13 (29%) patients with small cell lung carcinoma and
11
(25%)
patients
with
breast
cancer,
while
the
histology
of
the
remaining
patients
was
diverse
(9%
CNS
primary,
7%
non-small cell lung cancer, 7% lymphoma and some cases of
melanoma and nasopharyngeal carcinoma). In our study, the
histology of 82% patients was adenocarcinoma. Such homo-
geneity
in
the
histology
of
our
patients
might
make
our
results different from those of the previous studies. It is demon-
strated by the result that the median survival of the MHA arm
was
also
longer
than
that
of
the
M
arm
(23.9
vs
10.4
weeks,
P = 0.038) in patients with adenocarcinoma of the lung in the
subgroup analysis. This improvement in survival with combi-
nation chemotherapy deserves to be noted, as adenocarcinoma
is a less sensitive tumor and shows unsatisfactory results with
intrathecal chemotherapy.
Even though the five patients with small cell lung carcinoma
were excluded from the analysis, the response rate of the MHA
arm exceeded that of the M arm (27.3 vs 14.3%, P = 0.302), but
did not reach significance. We think that the disappearance of
statistical significance is partially due to the reduction in the
number of patients and the contribution of the patients with
small cell lung carcinoma to the response rate of the MHA arm
might be significant. Moreover, the superiority of the com-
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612 Combined vs single intrathecal CTX
bination treatment was not proven in a multivariate analysis.
Therefore, it needs to be discussed cautiously whether the
combination regimen is more beneficial for the response rate
and survival in solid tumor LMC.
The adverse effects encountered in the two treatment arms
were not so severe as to require discontinuation of the intra-
thecal treatment. The incidence and degree of side effects were
not different significantly between the two arms. A series of
previous studies also found that the addition of other drugs to a
methotrexate single regimen did not increase neurological or
systemic toxicities (4). Even in a trial of a combined regimen
consisting of methotrexate/ara-C/thiotepa (3), no unusual or
severe toxic conditions were observed, although the drugs were
co-administered at full doses.
We selected ara-C as an add-on agent with methotrexate in
our study. Although ara-C has been thought to be ineffective as
part of systemic combination chemotherapy in patients with
non-lymphomatous solid tumors, few effective additive agents
except ara-C in the intrathecal treatment of LMC were availa-
ble at the start of this study.
Ara-C has not been considered for the intrathecal chemother-
apy of LMC in solid tumors, mainly because the combination
treatment was not more effective than the single regimen treat-
ment in a few randomized prospective trials. However, ara-C is
an easily available and tolerable antineoplastic drug. In our
study, the addition of ara-C made a noticeable improvement in
the cytological response of malignant cells and the overall sur-
vival without increasing significant adverse effects. Therefore,
we think that the possibilities of a combination regimen includ-
ing
methotrexate
and
ara-C
should
be
reassessed
carefully.
The absence of an alternative neoplastic drug which is easily
available at present also makes this suggestion reasonable.
Recently, the promising results of a study using sustained-
release cytarabine (10) give indications as to the effectiveness
of ara-C in solid tumor LMC.
In conclusion, the addition of ara-C to methotrexate showed
greater effectiveness than methotrexate single regimen for
intrathecal chemotherapy of solid tumor LMC in our study,
which was discordant with the results of previous randomized
prospective studies. We suggest that this discrepancy is due to
the differences in the response criteria and the population char-
acteristics. We therefore recommend that a further randomized
prospective comparison should be performed for combination
versus single regimen intrathecal chemotherapy for patients
with homogeneous characteristics to prove the possible superi-
ority of the combination regimen of ara-C and methotrexate
over the single regimen, as shown in this study.
Acknowledgment
This work was supported by the Korea Science and Engineer-
ing Foundation (KOSEF) through MTRC.
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