J Neurooncol (2014) 119:361–368 DOI 10.1007/s11060-014-1486-2
CLINICAL STUDY
Concurrent intrathecal methotrexate and liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective cohort study Brian J. Scott • Vincent A. van Vugt • Toni Rush • Tiffany Brown • Clark C. Chen • Bob S. Carter • Richard Schwab • Paul Fanta • Teresa Helsten Lyudmila Bazhenova • Barbara Parker • Sandeep Pingle • Marlon G. Saria • Bradley D. Brown • David E. Piccioni • Santosh Kesari
•
Received: 10 September 2013 / Accepted: 19 May 2014 / Published online: 19 June 2014 Ó Springer Science+Business Media New York 2014
V. A. van Vugt T. Rush T. Brown B. D. Brown D. E. Piccioni S. Kesari (&) Department of Neurosciences, Moores UCSD Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, USA
IT liposomal cytarabine plus IT methotrexate with dexamethasone premedication. Patient characteristics, survival outcomes and toxicities were determined by systematic chart review. Thirty subjects were treated during the study period. The most common cancer types were breast 15 (50 %), glioblastoma 6 (20 %), and lung 5 (17 %). Cytologic clearance was achieved in 6 (33 %). Median nonglioblastoma overall survival was 30.2 weeks (n = 18; range 3.9–73.4), and did not differ significantly by tumor type. Median time to neurologic progression was 7 weeks (n = 8; range 0.9–57), with 10 subjects (56 %) experiencing death from systemic disease without progression of LM. Age less than 60 was associated with longer overall survival (p = 0.01). Six (21 %) experienced grade III toxicities during treatment, most commonly meningitis 2 (7 %). Combination IT chemotherapy was feasible in this small retrospective cohort. Prospective evaluation is necessary to determine tolerability, the impact on quality of life and neurocognitive outcomes or any survival benefit when compared to single agent IT chemotherapy.
T. Rush Department of Epidemiology and Biostatistics, San Diego State University, Hardy Tower 119, 5500 Campanile Dr, San Diego, CA 92182-4162, USA
Keywords Leptomeningeal metastases Central nervous system metastasis Intrathecal chemotherapy Solid tumor metastasis
C. C. Chen B. S. Carter Department of Neurosurgery, Moores UCSD Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA
Introduction
Abstract Leptomeningeal metastasis (LM) from solid tumors is typically a late manifestation of systemic cancer with limited survival. Randomized trials comparing single agent intrathecal methotrexate to liposomal cytarabine have shown similar efficacy and tolerability. We hypothesized that combination intrathecal chemotherapy would be a safe and tolerable option in solid tumor LM. We conducted a retrospective cohort study of combination IT chemotherapy in solid tumor LM at a single institution between April 2010 and July 2012. In addition to therapies directed at active systemic disease, each subject received B. J. Scott (&) Department of Neurology, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805, USA e-mail:
[email protected]
R. Schwab P. Fanta T. Helsten L. Bazhenova B. Parker Department of Medicine, Division of Hematology and Oncology, Moores UCSD Cancer Center, 3855 Health Sciences Drive, MC-0987, La Jolla, CA 92093, USA S. Pingle M. G. Saria S. Kesari Translational Neuro-oncology Laboratories, Moores UCSD Cancer Center, 3855 Health Sciences Drive, MC 0819, La Jolla, CA 92093, USA
The leptomeningeal space is a relatively uncommon and advanced site of metastatic spread for solid tumors. The incidence of meningeal dissemination varies by tumor histology (5–15 %), most commonly occurring in breast, lung, melanoma and high-grade glial neoplasms [1–3]. There are a number of treatment options for leptomeningeal metastases (LM), but the high incidence of concurrent
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progressive systemic cancer, poor functional status, or cerebrospinal fluid (CSF) flow obstruction often temper the decision to pursue aggressive therapies. Treatment of LM may include one or more of the following: intrathecal (IT) chemotherapy, intravenous (IV) chemotherapy, regional or craniospinal irradiation, or CSF diversion. The CSF penetration of IT chemotherapy is limited if there is bulky leptomeningeal disease or blockage of CSF flow [4]. Palliative radiation therapy may be used to treat sites of bulky disease, or to alleviate CSF obstruction [5]. CSF diversion with ventriculoperitoneal shunt (VPS) is an option in cases with impaired circulation of CSF [6]. VPS with a programmable or manual ‘on/off’ valve allows periodic administration of chemotherapy in patients with symptomatic CSF outflow obstruction [7]. In the absence of bulky LM or untreated CSF outflow obstruction, IT chemotherapy is a treatment option that permits higher concentrations of chemotherapeutic agents into the CSF space with limited hematologic toxicity. For solid tumor LM, the median survival with single-agent IT chemotherapy using methotrexate, thiotepa, cytarabine or liposomal cytarabine is 3–4 months [8–11]. In breast cancer, high dose IV methotrexate has been compared to IT methotrexate in the treatment of LM with available data suggesting similar survival outcomes and a lower incidence of treatment-associated meningitis [11, 12]. The limited efficacy observed in treating LM with IT chemotherapy may be due to dose-limiting toxicities or poor CSF flow producing inadequate concentrations of drug at the target site. Alternatively, there may be inherent chemoresistance in solid tumor LM. The limited effectiveness of monotherapy may be overcome by combining multiple IT chemotherapeutic agents with different mechanisms, a strategy that has successfully been employed in the treatment of other cancers [13]. Systemic high-dose IV MTX and cytarabine have been used concurrently in the treatment of CNS lymphoma with improved response and survival compared to MTX alone [14]. Combination drug trials for LM have been performed with the non-lyposomal form of IT cytosine arabinoside (Ara-C) and IT MTX, as well as with IT MTX and oral temozolomide (TMZ). Combining Ara-C with MTX had no added benefit over single-agent chemotherapy with more toxicity [15]. The addition of TMZ to liposomal cytarabine resulted in a prohibitively high incidence of hematologic toxicity [16]. To the best of our knowledge, the combination of IT MTX and liposomal Ara-C has not been reported. We reviewed the tolerability of combination IT chemotherapy in individuals with solid tumor LM.
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Methods A retrospective cohort study of consecutive subjects newly diagnosed with LM between April 2010 and July 2012 was conducted at the University of California, San Diego Moores Cancer Center. Subjects consented to have clinical information shared for research purposes, and data collection was performed using standardized data collection forms. Inclusion criteria Subjects included were C18 years old, with a histologically confirmed solid tumor diagnosis. Subjects were required to have clinical signs and symptoms suspicious for LM (headache, confusion, neurological deficits) and either CSF cytology positive for malignancy, contrast-enhanced neuroimaging findings consistent with LM or both. Radiographic evidence of LM was determined by a consensus review between the neuro-oncologist and neuroradiologist. Treatment of LM Following LM diagnosis, an intraventricular catheter with Ommaya reservoir was placed for administration of IT chemotherapy or lumbar spinal taps were performed. All received treatment with concurrent IT methotrexate (12 mg) and IT liposomal cytarabine every two weeks. During the initial study period, 25 mg of IT liposomal cytarabine was given every 2 weeks, and later subjects received a dose of 50 mg. The most recently diagnosed patients in the cohort received triple IT chemotherapy with the addition of thiotepa (10 mg) every 2 weeks. Radioisotope CSF flow studies were not routinely performed. In cases clinically suspected to have hydrocephalus, a combined VPS and Ommaya reservoir with manual on/off valve for administration of IT chemotherapy was placed as described previously [7]. Treatment of bulky ([3 mm) or nodular LM, and/or active brain metastasis with radiation therapy was executed at the discretion of the treatment team, and individuals undergoing cranial irradiation therapy were not excluded. Subjects received oral dexamethasone 4 mg BID for 5 days starting the day before IT chemotherapy. Response to treatment was assessed via CSF cytology every 2 weeks, prior to administration of each IT treatment. Brain and/or spine MRI were performed at 2-month intervals in cases where radiographic abnormalities were present at diagnosis.
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Treatment of active non-LM Cancer Additional therapies including surgery, radiation therapy, and/or systemic chemotherapy were administered at the discretion of the primary oncologist. Therapy directed at non-LM cancer was not modified or held for IT chemotherapy.
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([30 day) grade III or IV toxicity; (3) clinical or radiographic progression of cancer (LM or non-LM). Subjects were followed clinically until death or the end of the study for a minimum of 6 months.
Results
Data collection
Patient characteristics
A detailed chart review was performed to obtain patient characteristics, treatment information and survival data using a standardized data collection form. Time to LM diagnosis was calculated as the interval between the initial cancer diagnosis and the diagnosis of LM (date of positive CSF cytology or abnormal MRI). CSF parameters (cell count, protein, glucose, lactate) and CSF cytology were obtained from the initial pretreatment lumbar puncture. CSF cytology was assessed on subsequent IT treatment days in cases that had a positive or atypical CSF cytology on initial examination. Cytologic response was defined as conversion from positive to negative CSF cytology measured on 2 or more consecutive CSF cytologies C4 weeks apart. Clinical response was defined as any improvement in neurological symptoms that were present at the time of initial treatment, assessed on subsequent treatment visits at 2 week intervals. Clinical stability was defined as no measurable worsening or improvement of clinical neurological symptoms from the initial clinic visit compared to subsequent IT treatment visits. Time to neurological progression was measured as the time interval between the diagnosis of LM (as above) and the visit documenting clinical or radiographic progression of LM. To facilitate comparisons with previous LM studies, subjects with GBM were excluded from the overall survival and time to neurological progression analysis. Overall survival was measured as the time interval between the diagnosis of LM (as above) and the date of death. Adverse events were assessed by reviewing clinic notes and laboratory results during the treatment period, and reported using the common terminology criteria for adverse events (CTCAE) version 4.0 [National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, DHHS. May 29, 2009 NIH publication # 09-7473]. All adverse events that occurred during treatment with IT chemotherapy were reported, without making causal inferences.
Thirty subjects were newly diagnosed and treated for LM during the study period. Patient characteristics are summarized in Table 1. The median age was 57, and median Karnofsky Performance Status (KPS) was 70–80. The most common primary tumor was breast cancer (50 %), followed by glioblastoma (20 %) and lung cancer (17 %). Common presenting symptoms included neuropathy/ radiculopathy (57 %), headache (43 %), and altered mental status (14 %). The median time from initial cancer to LM diagnosis was 121.6 weeks. Breast and other cancers presented substantially later following initial cancer diagnosis (184.5 and 158.7 weeks) compared to GBM and lung cancer (97.1 and 18.7 weeks) respectively. Most subjects (82 %) had at least one other site of active cancer at the time of LM diagnosis, most commonly parenchymal CNS or bone disease, requiring additional systemic chemotherapy or radiation. Fifteen of the subjects were diagnosed by positive CSF cytology, while the remainder had clinical symptoms and MRI findings consistent with LM. CSF cell count was elevated ([5 cells per high-power field) in 22/29 (76 %), with a median cell count of 123 cells per high power field (range 3–5367; IQR 6-203). Positive CSF cytology did not necessarily correlate with elevated CSF cell count, as 4 of the 7 cases without a CSF pleocytosis had a positive CSF cytology. CSF protein was elevated ([50 mg/dL) in 15/29 (52 %), with a median CSF protein of 64 mg/dL (range 7–282; IQR 27.5–81.5). Median CSF lactate was 25.2 mg/dL (range 16.5–52.8; IQR 20.8–31), and found to be elevated (normal range 10.0–22.0 mg/dL) in 18/27 (66.7 %). Fourteen subjects (47 %) received radiation therapy to the brain and/or spine in some form (whole brain radiation, spine radiation, intensity modulated radiation therapy, or stereotactic radiosurgery) while receiving IT chemotherapy. Four subjects (13 %) underwent placement of a VPS with on/off valve and Ommaya reservoir to alleviate CSF outflow obstruction, and there was one case of VPS infection requiring shunt replacement. One subject underwent surgery for resection of a symptomatic cerebellar metastasis. Dual IT chemotherapy (liposomal cytarabine 25 or 50 mg and MTX 12 mg) was administered in 80 %, and the remaining 20 % of subjects received triple IT
Discontinuation of treatment Treatment was continued until one of the following events occurred: (1) cytologic clearance C2 months; (2) persistent
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Table 1 Patient characteristics n (range) Age KPS Median time to LM Dx (weeks)
57 (25–69) 80 (40–90) 123.9 (0.3–778.3) n (%)
Presenting symptoms Headache
12 (43)
Cranial Neuropathy Radiculopathy
12 (43) 5 (18)
Altered Mental Status
4 (14)
Seizure
2 (7)
Cancer type Breast
15 (50)
GBM
6 (20)
Lung
5 (17)
Other
4 (13)
Active non-LM cancer 1° Brain (GBM) n = 6
6 (100)
Systemic Cancer n = 24
14 (58)
Bone
12 (50)
Brain Mets
12 (50)
Lung (2 primary, 5 mets)
7 (29)
Liver
7 (29)
Spleen Peripheral nerve
1 (4) 1 (4)
Peritoneum
1 (4)
Concurrent treatment IT MTX
30 (100)
IT DepoCyt
30 (100)
Systemic chemo
22 (73)
WBRT
10 (33)
IT Thiotepa
6 (20)
Regional brain RT
4 (13)
Spine RT
4 (13)
VP Shunt
4 (13)
Surgery
1 (3)
chemotherapy with concurrent liposomal cytarabine 25 mg, MTX 12 mg and thiotepa 10 mg. Liposomal cytarabine was given alone for the first 1–2 cycles in 4 subjects, and the first 3 cycles in 1, with IT MTX added thereafter. A median of 3.5 IT treatments were completed. The median total dose of IT liposomal cytarabine was 150 mg (n = 30, range 25–450). The median total dose of IT MTX was 42 mg (n = 30, range 12–84). The median total dose of IT thiotepa for the triple IT group was 20 mg (n = 6, range 10–40).
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Fig. 1 Kaplan–Meier analysis of overall survival in non-GBM LM
Response Clinical response to treatment was assessable in 29 subjects. Eleven (38 %) had clinical improvement, 5 (17 %) had stabilization of symptoms, and 13 (45 %) had clinical progression as their best response. Responders had a median OS of 31.5 weeks compared to 16.5 weeks in nonresponders (p = 0.47). Clinical improvement was most common among breast cancer LM (54 %), and least common in GBM (20 %) and lung cancer (20 %). There was no difference in the frequency of response when comparing those who did 6/10 (60 %) versus did not (10/19 (53 %) receive whole brain radiation therapy in the course of their treatment. CSF cytologic clearance was achieved in 6/18 (33 %) without differences in the rate of cytologic clearance between tumor types. Survival Survival and time to neurologic progression was assessed in non-GBM subjects only (n = 24). The median time to neurological progression was 12.3 weeks (0.9–73.4; n = 12), and median overall survival was 30.2 weeks (3.9–73.4; n = 18) (Fig. 1). Survival was similar for different primary tumor types (Table 2). Time to neurological progression was significantly shorter in the 3 patients who underwent VPS placement for symptomatic elevation of intracranial pressure (p = 0.001). Six-month LM-progression free survival was 50 % (GBM excluded), and 6 month overall survival was 67 %. Twelve-month OS was 28 %. Overall survival was significantly longer in subjects less than 60 years old (Fig. 2) (46.3 weeks (11.1–73.4; n = 8) versus 16.5 weeks (3.9–55.9; n = 10); p = 0.01). In nonGBM subjects, initial KPS C 70 tended to be associated with longer survival (27.6 weeks (11.1–73.4; n = 11) with KPS C 70 versus 10.9 weeks (3.9–69.4; n = 7) with KPS \ 70; p = 0.34) (Table 3).
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Table 2 Survival hazard ratios excluding GBM patients, n = 24
Table 3 Survival by primary tumor type (GBM excluded)
Characteristic
Primary tumor
Survival p value
Median time to neurologic progression weeks (range)
(n)
HR
(95 %CI)
Breast
13.4 (0.9–73.4)
\60
0.25
(0.08, 0.73)
Lung
14.4
C60
1.00
–
Other Total
5.3 12.3 (0.9–73.4)
\70
1.00
–
C70
0.62
(0.23, 1.68)
0.72
(0.18, 2.77)
Lung
2.36
(0.55, 10.11)
Other
1.00
–
Age
KPS
Tumor type Breast
Active sys CA
0.01
0.34
0.97 1.02
Yes Brain mets at dx
1.00 0.98
Yes ICP elevation
(0.38, 2.76) –
0.96
No
(n)
10
33.2 (10.1–73.4)
10
1
22.6 (3.9–52.1)
5
1 12
40.4 (27.6–55.9) 30.2 (3.9–73.4)
3 18
Table 4 Toxicities during treatment
0.13
No
Median OS weeks (range)
1.00
n (%) No reported toxicity
18 (64)
CTCAE Grade I, II
13 (46)
CTCAE Grade III
6 (21)
Meningitis
2 (7)
Seizure
1 (4)
(0.37, 2.55)
Neutropenia/Thrombocytopenia
1 (4)
–
Pneumonitis
1 (4)
Herpes Zoster
1 (4)
VP Shunt Infection
1 (4)
0.61
No
0.72
(0.20, 2.58)
Yes
1.00
–
Treatment Interruption Due to Toxicity Median duration of delay (days, range)
3 (10) 33 (7–52?)
Toxicity Toxicities throughout the course of treatment were assessable in 28 subjects, and are summarized in Table 4. There was no reported toxicity in 64 % of subjects. Four subjects experienced mild to moderate headache following IT therapy. There were 6 grade III toxicities. Meningitis was the most common (7 %). Hematologic adverse effects occurred in 2 subjects, one of which was grade III. Seizures occurred in a subject with parenchymal brain metastases. Treatment was interrupted due to toxicity in 3 cases (meningitis, herpes zoster, and mucositis) for a median of 33 days. Leukoencephalopathy on brain MRI was assessable in 24 subjects. Sixteen (67 %) developed mild to moderate leukoencephalopathy during treatment. Fig. 2 Kaplan–Meier analysis of overall survival stratified by Age (\60 vs C60 years old)
Discussion
To date, 18/24 non-GBM subjects have died, and of those, the cause of death was progression of LM in 6 (33 %), and progressive systemic cancer in 10 (56 %). Treatment was stopped in 4/24 (17 %) after 2 months of documented cytologic response, or resolution of abnormal enhancement on MRI.
Solid tumor LM is a challenging neurologic manifestation of cancer with no satisfactory treatment options and poor survival. If treatment is pursued, it most commonly involves palliative radiation therapy and consideration of single agent IT chemotherapy. Often, a diagnosis of LM leads to a decision to avoid aggressive treatments due to historically limited response to treatment and the potential
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Table 5 Previous single agent and combination therapy LM trials Study
# patients
Histology
Treatment
Toxicity overall (Gr III/IV)
Meningitis (%)
Clinical response (%)
Cytologic response (%)
Median OS (weeks)
Combined agent Current study
30
ST, G
IT MTX ? IT LC
21
7
55
33
30.2
Groves et al. [16] Kim et al. [19]
11 26
ST, Ly ST
LC ? TMZ IT MTX, IT C, HC
81 NR
45
17 45
9 38.5
9 18.6
29
ST
IT MTX
NR
61
13.8
10.4
20
ST, G, Ly
IT MTX ? IT C
NR
10
73
45
7
22
ST, G, Ly
IT MTX
NR
18
59
61
12
Chamberlain [20]
80
ST, Ly, G
IT LC (Ommaya)
22.5
17.5
IT LC (lumbar)
22.5
15
Lin et al. [7]
24
ST, G, Ly
IT MTX, T or LC ? RO-VPS
8.3 % VPSrelated
59
61
31
24
ST, G, Ly
IT MTX, T or LC
Boogerd et al. [11]
17
B
IT MTX
47
12
86
35
18.3
18
B
IV MTX
6
0
74
31
ST, G
IT LC
23
26
26
15
30
ST, G
IT MTX
19
20
23
11.1
28
ST, Ly
IT MTX
57
32
29
15.9
24
ST, Ly
IT T
33
13
33
14.1
Hitchins et al. [15] Single agent
40
Glantz et al. [9] Grossman et al. [8]
67
19.5 30.3
Histologies: ST breast, lung, melanoma, gastrointestinal, other solid tumor, Ly lymphoma/leukemia, G glioma; B breast only Treatment: MTX methotrexate, T thiotepa, C cytarabine, LC liposomal cytarabine, TMZ oral temozolomide, HC hydrocortisone Route: IT Intrathecal, IV Intravenous RO-VPS Reservoir-on/off ventriculoperitoneal shunt, NR not reported
for added patient discomfort with additional therapy. Here, we report a multi-agent IT chemotherapeutic regimen that was well-tolerated in this small cohort, and may be administered in the ambulatory setting at 2 week intervals. The current study population reflects a consecutive sampling at a single institution, and is representative of patients with solid tumor LM in terms of age and frequency of concurrent active systemic cancer. The number of glioma patients is higher than would be expected in the general population, potentially due to institutional referral bias. The significantly longer survival in subjects less than 60 may reflect a better response to combination IT treatment in this population, and warrants further investigation. A selection bias for treating younger patients more aggressively cannot be excluded. Longer survival for younger patients is not explained by differences in primary tumor between groups, as they were represented similarly. Although it is possible that there was a bias toward excluding subjects due to an extremely low performance status from treatment with IT chemotherapy, low KPS was
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not an exclusion criterion. Thus there are individuals included in this study with KPS as low as 40 that would not typically be enrolled in LM trials due to poor performance status. This would be expected to result in shorter survival outcomes in our population, as low KPS has been associated with poorer overall survival [17]. In spite of this, the median overall survival of 30.2 weeks and a 6 month overall survival of 67 % compare favorably to historical studies of combination IT chemotherapy (Table 5) [15, 16, 19]. The present cohort includes 50 % breast cancer LM, which tends to present later than lung cancer or glioma LM, and is associated with a longer median overall survival [18]. Although many previous LM trials have included CNS lymphoma, it was not included in the present cohort because of established IV methotrexate-based chemotherapy for CNS lymphoma that is the currently accepted first line of therapy [14]. Studies investigating combined IT chemotherapies have shown no survival benefit over treatment with a single agent, and prohibitively high levels of CNS toxicity [15,
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16]. The present cohort combining IT MTX and liposomal Ara-C had less meningitis than has been previously reported with single-agent IT liposomal cytarabine [9, 20] (7 versus 10–45 %). Aggressive treatment with high-dose dexamethasone before and after IT chemotherapy likely contributed to the low rate of chemical meningitis in the current study population, was well-tolerated, and was not associated with any significant adverse events. There are several potential limitations to this study. The single arm design limits the ability to directly compare these results with a matched population. The retrospective analysis introduces the potential for reporting biases and incomplete clinical follow-up and laboratory assessments, although this was minimized because each subject had a clinical assessment in neuro-oncology clinic every 2 weeks during IT treatments. The overall serious complication rate in the present study is lower than what has been previously reported with IT MTX alone (21 versus 31–81 %) [10]. However, the lack of predetermined toxicity reporting in the present study introduces the potential for an underestimation of toxicities and adverse events. Two-thirds of subjects developed leukoencephalopathy in the course of treatment. This is higher than the incidence reported with liposomal cytarabine alone [20], but similar to what has been observed with single-agent IT MTX [21]. Direct comparison of survival outcomes with previous studies is limited by variation among the relative frequencies of solid tumor LM, and differences in the diagnostic and other inclusion criteria. In addition, clinical response assessments are not uniform between studies, which contributes to the highly variable response rates reported (Table 5). The retrospective study design and small number of patients made it impossible to detect or draw conclusions about differences in survival among the various solid tumor types or histologies, the impact of hormone receptor status or other primary tumor characteristics on survival and responses rates, or the impact of functional status on survival. A larger prospective study with a single-agent control arm is needed to answer these and other clinically important questions.
Conclusions Combination chemotherapy in LM has been avoided due to reports of increased toxicity compared to single agent IT or IV chemotherapy. In contrast to previous reports, the present study results demonstrate that combined IT chemotherapy may be feasible. There was comparatively better survival with combination IT chemotherapy in this cohort for subjects less than 60 years old. Further investigation is warranted to determine whether combination IT chemotherapy with
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liposomal cytarabine, methotrexate and thiotepa confers any added survival when compared to treatment with single agent IT therapy or radiation alone. The tolerability of combination IT chemotherapy in this study suggests that other novel IT combination therapies could be considered in the interest of advancing the treatment of solid tumor LM. In addition, palliative care endpoints, pre and post-treatment radiographic assessment of leukoencephalopathy, neurocognitive and quality of life assessments will need to be done in future prospective studies to understand the impact of treatment on these measures [22]. Due to the observed differences in response to therapies, biomarker directed treatment may have a significant role in selecting subjects. Acknowledgments This work was supported in part by Grants from NIH (NIH 3P30CA023100-25S8) to S. Kesari. Conflict of interest
The authors report no conflict of interests.
References 1. Kesari S, Batchelor TT (2003) Leptomeningeal metastases. Neurol Clin 21(1):25–66 2. Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM (2010) Leptomeningeal metastases in the MRI era. Neurology 74(18):1449–1454 3. Balm M, Hammack J (1996) Leptomeningeal carcinomatosis presenting features and prognostic factors. Arch Neurol 53(7):626–632 4. Chamberlain MC, Kormanik PA (1997) Prognostic significance of coexistent bulky metastatic central nervous system disease in patients with leptomeningeal metastases. Arch Neurol 54(11):1364–1368 5. Chamberlain MC, Corey-Bloom J (1991) Leptomeningeal metastases: 111indium-DTPA CSF flow studies. Neurology 41(11):1765–1769 6. Omuro AM, Lallana EC, Bilsky MH, DeAngelis LM (2005) Ventriculoperitoneal shunt in patients with leptomeningeal metastasis. Neurology 64(9):1625–1627 7. Lin N, Dunn IF, Glantz M et al (2011) Benefit of ventriculoperitoneal cerebrospinal fluid shunting and intrathecal chemotherapy in neoplastic meningitis: a retrospective, case-controlled study. J Neurosurg 115(4):730–736 8. Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS (1993) Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. eastern cooperative oncology group. J Clin Oncol 11(3):561–569 9. Glantz MJ, Jaeckle KA, Chamberlain MC et al (1999) A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5(11):3394–3402 10. Bokstein F, Lossos A, Siegal T (1998) Leptomeningeal metastases from solid tumors: a comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy. Cancer 82(9):1756–1763 11. Boogerd W, van den Bent MJ, Koehler PJ et al (2004) The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer 40(18):2726–2733
123
368 12. Glantz MJ, Cole BF, Recht L et al (1998) High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16(4):1561–1567 13. Carrick S, Parker S, Thornton CE, Ghersi D, Simes J, Wilcken N (2009) Single agent versus combination chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev. doi:10.1002/ 14651858.CD003372.pub3 14. Ferreri AJ, Reni M, Foppoli M et al (2009) High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374(9700):1512–1520 15. Hitchins RN, Bell DR, Woods RL, Levi JA (1987) A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 5(10):1655–1662 16. Groves MD, DeGroot J, Loghin M et al (2011) A phase I study of temozolomide and intrathecal liposomal cytarabine in patients with neoplastic meningitis. Neuro-oncology 13:43 17. Chamberlain MC, Johnston SK, Glantz MJ (2009) Neoplastic meningitis-related prognostic significance of the karnofsky performance status. Arch Neurol 66(1):74–78 18. Drappatz J, Batchelor TT (2007) Leptomeningeal neoplasms. Curr Treat Options Neurol 9(4):283–293
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J Neurooncol (2014) 119:361–368 19. Kim DY, Lee KW, Yun T et al (2003) Comparison of intrathecal chemotherapy for leptomeningeal carcinomatosis of a solid tumor: methotrexate alone versus methotrexate in combination with cytosine arabinoside and hydrocortisone. Jpn J Clin Oncol 33(12):608–612 20. Chamberlain MC (2012) Neurotoxicity of intra-CSF liposomal cytarabine (DepoCyt) administered for the treatment of leptomeningeal metastasis: a retrospective case series. J Neurooncol 109(1):143–148 21. Kim JY, Kim ST, Nam DH, Lee JI, Park K, Kong DS (2011) Leukoencephalopathy and disseminated necrotizing leukoencephalopathy following intrathecal methotrexate chemotherapy and radiation therapy for central nerve system lymphoma or leukemia. J Korean Neurosurg Soc 50:304–310 22. Chamberlain M, Soffietti R, Raizer J, Ruda` R, Brandsma D, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Junck L, van den Bent M, Wen PY, Jaeckle KA (2014) Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials. Neuro-oncology. doi:10.1093/neuonc/nou089
