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Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities
Journal of Clinical Neuroscience xxx (2015) xxx–xxx
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities Manisha Kak a, Rita Nanda b, Erika E. Ramsdale c, Rimas V. Lukas a,⇑ a
University of Chicago, Department of Neurology, 5841 S. Maryland Avenue, MC 2030, Chicago, IL 60637, USA University of Chicago, Section of Hematology and Oncology, Chicago, IL, USA c University of Virginia, Division of Hematology and Oncology, Charlottesville, VA, USA b
a r t i c l e
i n f o
Article history: Received 12 October 2014 Accepted 17 October 2014 Available online xxxx Keywords: Breast cancer Carcinomatous meningitis Chemotherapy Intrathecal therapy Leptomeningeal carcinomatosis Radiotherapy
a b s t r a c t Leptomeningeal metastasis (LM) in breast cancer patients confers a uniformly poor prognosis and decreased quality of life. Treatment options are limited and often ineffective, due in large part to limitations imposed by the blood–brain barrier and the very aggressive nature of this disease. The majority of studies investigating the treatment of LM are not specific to site of origin. Conducting randomized, disease-specific clinical trials in LM is challenging, and much clinical outcomes data are based on case reports or retrospective case series. Multiple studies have suggested that chemo-radiotherapy is superior to either chemotherapy or radiation therapy alone. Attempts to overcome current obstacles in the treatment of breast cancer LM hold promise for the future. We review the epidemiology, diagnosis, and prognosis of LM in breast cancer, and discuss the treatment options currently available as well as those under investigation. Ó 2014 Elsevier Ltd. All rights reserved.
1. Epidemiology Breast cancer affects one in eight women. It is estimated that 230,000 women in the USA will be diagnosed with breast cancer in 2014 [1]. Leptomeningeal metastasis (LM) can complicate virtually any malignancy, and breast carcinoma is the most common solid tumor associated with it [2,3]. Estimates of the incidence of LM in breast cancer patients in clinical series range from 1–8% [4,5], with autopsy series revealing an incidence as high as 16% [6]. Triple-negative breast cancer appears to have a higher likelihood of LM [7], and a shorter interval between initial diagnosis and development of LM [8].
2. Diagnosis The clinical presentation of LM is highly variable, as any level of the neuro-axis may be affected. The gold standard for diagnosis of LM is demonstration of malignant cells in cerebrospinal fluid (CSF), although the false negative rate may be substantial and improved sensitivity may rely on repeated sampling of the CSF [2]. Several studies have examined the diagnostic usefulness of other CSF measurements with mixed results. Hypoglycorrhachia (<50% of LM) ⇑ Corresponding author. Tel.: +1 773 834 9026; fax: +1 773 702 7485. E-mail address: [email protected] (R.V. Lukas).
[2,4,5,9–11], lymphocytic pleocytosis (25–64% of LM), and elevated opening pressures (50% of LM) are non-specific, but raise suspicion for LM in the proper clinical setting [11]. Also non-specific, elevated CSF protein was more sensitive in some studies [11,12], correlating with the diagnosis in 60–90% of cases. Other CSF biomarkers investigated include lactate dehydrogenase, carcinoembryonic antigen, lactate, oligoclonal bands, B-glucuronidase, beta-2 microglobulins, vascular endothelial growth factor, and cancer antigen 15-3 [2,13,14–16], but are not routinely used due to similarly suboptimal sensitivity and specificity. Neuroradiologic criteria for the diagnosis of LM have played a growing role since the advent of MRI [17]. The characteristic finding on MRI is meningeal enhancement, best noted at the skull base between cerebellar folia, along cranial nerves, and around the spinal cord and nerve roots (Fig. 1). MRI findings are abnormal in 75–90% of patients with cytology-positive CSF [11,18]. One retrospective review of 187 LM patients showed that 53% of patients were diagnosed by imaging, 23% by cytology, and 24% by both [30]. Most experts agree that typical MRI findings in conjunction with a consistent clinical picture fulfill diagnostic criteria for LM [19].
3. Prognosis Unfortunately, outcomes for breast cancer patients with LM remain dismal: rates of response to therapy and overall survival
http://dx.doi.org/10.1016/j.jocn.2014.10.022 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022
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M. Kak et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
(A)
(B)
definitively been shown to correlate with outcomes [2,4,5,7,11,12]. Other potential prognostic factors include age [5,7,12], control of systemic disease [12], histological grade [11], presence of cranial neuropathies [5], presence of lung metastases [5,11], no response to systemic or intrathecal therapy [10], and number of prior chemotherapy regimens [10,11,21]. Evaluation of tumor tissue for the presence of estrogen receptors, progesterone receptors, and human epithelial receptor 2 (HER2) is standard practice in breast cancer as these are both prognostic and predictive markers influencing management. The importance of receptor status in breast cancer LM mirrors its importance in breast cancer in both systemic disease as well as brain metastases [22]. Some studies show that HER2+ LM has a better OS while triple-negative patients have poorer OS [20]. However, other studies suggest that patients with triple-negative disease may only appear to have worse outcomes because they have shorter time until diagnosis of LM [8]. Suggestion has been made for serial evaluation of receptor status on these cells to guide clinical management [23]. Median survival in patients with LM from solid tumors ranges from 6–8 weeks in untreated patients, and 8–30 weeks in treated patients. Early studies combining patients with various primary tumors suggested that those with LM and breast cancer primaries have a higher response to treatment (up to 60% improving or stabilizing with chemotherapy and/or radiation therapy) and longer median survivals than those with other primaries (7 months versus 8–30 weeks) [2,4,11,20,24]. 4. Treatment
(C)
Therapeutic trials for solid tumor LM are small and include heterogeneous patient populations. Accrual is challenging because of the relatively low incidence and rapidly progressive nature of the disease. The majority of data available on efficacy and outcomes are from non-randomized or observational studies in patients who were not uniformly treated and have a wide range of tumor types. Additionally, endpoints have varied between trials, making it challenging to determine the optimal management of patients with LM. Modalities used in patients with LM to date include radiation therapy (RT), systemic therapy, and intrathecal therapy. 4.1. RT
Fig. 1. (A) Sagittal T1-weighted post-contrast MRI of the brain revealing enhancing lesions deep within the sulci supratentorially (solid arrow), on the cerebellar surface (dashed arrow), and at the anterior surface of the fourth ventricle (dashed arrow). (B) Axial T1-weighted post-contrast MRI of the brain showing enhancing lesions on the cerebellar surfaces (arrow). (C) Sagittal T1-weighted post-contrast MRI of the lumbosacral spine revealing ‘‘sugar coating’’ of the surface of the spinal cord (solid arrow) and bulkier enhancement of the cauda equina (dashed arrow).
(OS) have not markedly changed, despite dramatic improvement in outcomes for those with visceral disease. Outside of performance status (PS), no consistent set of prognostic or predictive indicators have been elucidated to guide management. PS has demonstrated prognostic significance in a number of studies [7,10,11,20,21]. Pre-treatment CSF markers for prognostication have not
Craniospinal RT plays an important role in the treatment of central nervous system (CNS) metastases because it addresses the entire CSF space. However, it is often not used to treat LM due to significant toxicity, particularly in patients who may have overlapping RT fields from prior chest wall RT. A more focal approach is often employed to limit toxicity. Whole brain RT, alone or followed by chemotherapy, is used to treat a substantial portion of the CSF space, palliate symptoms, and improve quality of life [5,10]. Focal RT is frequently used to treat bulky disease as other treatment modalities may have limited effect on regions of large CSF tumor burden. Focal RT can be administered either in a fractionated manner or as a single dose via stereotactic radiosurgery. No broad guidelines exist and decisions are made on a case by case basis. In turn, it is unclear whether increased doses or alternate dosing schedules of radiation may be appropriate in certain tumor subtypes. Studies have suggested that tumors arising in patients with deleterious germline BRCA1/2 mutations are more sensitive to the DNA-damaging effects of RT [19]. There exists mixed data regarding the role of receptor status on sensitivity to RT. Triple negative patients with intracranial metastases (not LM specifically) have high objective response rates to RT but shorter OS [25]. Other studies have not demonstrated receptor status to be predictive of outcome to hypofractionated RT [26].
Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022
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4.2. Systemic therapies Delivery of systemically administered treatments into CSF in therapeutic concentrations is limited by the blood–brain barrier (BBB) and blood–CSF barriers. The barrier between the CNS and the rest of the body is a complicated and dynamic system limiting the ability of many molecules, particularly large hydrophilic ones, from reaching the CNS in therapeutic concentrations. Despite this, large non-lipophilic agents which would presumably inadequately cross the BBB have been show to lead to radiographic responses in the CNS [27]. Our understanding of which systemically delivered agents are able to readily treat CNS malignancies continues to evolve, influencing the way this patient population is managed. In the following section we will discuss treatment of LM focusing primarily on breast cancer-specific LM trials (Table 1) and breast cancer-specific larger case series (Table 2). HER2 has proven to be a viable target in patients with HER2amplified breast cancer, leading to the United States Food and Drug Administration (FDA) approval of anti-HER2 therapies in these patients. It does not appear that the use of HER2 targeted therapies decreases the rate of CNS involvement [28]. Eighteen to 30% of advanced breast cancer patients receiving trastuzumab-based therapy develop brain metastases, and 4–19% of them develop LM, often while their systemic tumor burden responds [29,30]. This may be because trastuzumab does not effectively cross the BBB, or because of loss of HER2 amplification in the breast cancer cells that metastasize to the brain. However, patients with HER2 amplified breast cancer and CNS metastases, both in brain parenchyma and CSF, fare better than those who are HER2 negative [20,22]. This may be due to more favorable natural history, better CNS response to therapies, better extra-CNS response to therapy, or a combination of these factors. The large size of antibodies/antibody-drug conjugates precludes them from easily entering the CNS. Trastuzumab, the first and best studied of the anti-HER2 antibodies, has low penetration through the BBB with 300-fold lower concentration in human CSF compared to serum [31]. Means of increasing the BBB permeability of trastuzumab have been investigated in animal models [32]. There have been no trials investigating the role of systemically administered trastuzumab in the treatment of LM specifically to our knowledge. Pertuzumab, another anti-HER2 antibody, and adotrastuzumab emtansine, an antibody-microtubule inhibitor conjugate, also have not been evaluated specifically in LM or brain metastases. It is unclear what the CNS concentrations of these agents are when delivered intravenously. However, numerous retrospective studies have suggested potential benefit of systemic chemotherapy on response rates and OS of breast cancer patients with CNS metastases and LM [12,33,34].
To circumvent the BBB, lapatinib, a HER2/epidermal growth factor receptor dual tyrosine kinase inhibitor, has been investigated. When first approved, it was thought to effectively cross the BBB, but recent animal studies have shown that it is not always distributed in high concentrations in brain metastases [35]. One study conducted in mice showed the concentration of lapatinib in brain metastases was 7-fold to 9-fold higher in brain metastases compared to surrounding brain tissue, but still only 10–20% of the concentration measured in peripheral metastases [35]. Lapatinib has been shown to be active in combination with capecitabine, a 5-fluorouracil prodrug whose metabolites cross the BBB, when used in patients with HER2 positive breast cancer previously treated with trastuzumab [36]. When lapatinib was studied as a single agent in patients with progressive brain metastases, the response rate was limited (2.6 to 6%) in this refractory patient population [37]. However, the addition of capecitabine after progression on lapatinib alone yielded objective responses in 20% of patients. In patients with newly diagnosed brain metastases objective responses were seen in one-third to two-thirds of patients. Similar responses were not noted when combining lapatinib with other agents such as topotecan in this patient population [38]. While to our knowledge this agent has not been studied prospectively in LM it has apparent efficacy in HER2 positive breast cancer patients with brain metastases, suggesting the potential for response in LM patients, although this requires further study before being broadly applied. Literature on hormone antagonists and aromatase inhibitors in LM is sparse, and hormonal agents’ ability to penetrate the BBB has been minimally investigated thus far. Tamoxifen, an estrogen receptor antagonist, is a highly lipophilic agent that can cross the BBB and has enhanced ability to do so when metastases increase permeability. Significant and even cytotoxic concentrations of tamoxifen have been observed in brain tissue, and higher concentrations in brain tumor tissue [39]. Furthermore, prolonged progression free survival has been seen in anecdotal reports of breast cancer LM patients treated with various therapies targeted towards hormone receptors [40]. Temozolomide, an alkylating agent approved for gliomas, has been evaluated in breast cancer brain metastases with response rates ranging from 0 to 44% in breast cancer patients receiving temozolomide alone or in combination with whole brain RT, with the highest rates reported with combined chemo-radiotherapy [41]. While cases of LM responses in other solid tumors have been reported [42], there are no prospective trials and no case reports or case series specifically looking at temozolomide in breast cancer LM to our knowledge. Taxane-based chemotherapies such as paclitaxel and docetaxel are antimicrotubular agents effective in metastatic breast cancer, but have been proven to lack adequate CNS penetration [43].
Table 1 Breast cancer specific leptomeningeal metastasis trials Study (year)
Phase Patients Age, years
Boogerd et al. 1 (2004) [59] Orlando et al. 1 (2002) [47]
1 Jaeckle et al. (2001) [53]
35 13
56
Mean 49.6 vs 57.9 Range 30–67 (median 45)
Receptor
Treatment Interval b/w initial Dx and development of LM
Unknown Unknown Unknown Unknown
Range 28–74 Unknown Unknown (median 50)
LRT + IVC vs LRT + ITC IT thiotepa, MTX, hydrocortisone, cytarabine, oral folinic acid IT liposomal cytarabine
Overall survival
Progression Progression Response ratea free survival free survival at 12 mo
Mean 30.3 weeks N/A vs 18.3 weeks Mean 63 days N/A (range 1–278 days)
Mean 88 days
49 days
N/A N/A
19%
59% PR or SD vs 67% PR or SD 100% had SD or PD (no clinical response observed in any patients) 28% PR or CR
a According to the Response Evaluation Criteria In Solid Tumors. b/w = between, CR = complete response, Dx = diagnosis, IT = intrathecal, ITC = intrathecal chemotherapy, IVC = intravenous (systemic) chemotherapy, LM = leptomeningeal metastasis, LRT = local radiation therapy, MTX = methotrexate, N/A = not available, PR = partial response, PD = progressive disease, SD = stable disease, vs = versus, WBRT = whole brain radiation therapy.
Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022
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Study (year)
Patients
Age range, years
Receptor
HER status
Interval b/w initial Dx and development of LM
Treatment
Overall survival
Progression free survival
Progression free survival % in time
Relative responsea
Chmielowska et al. (2012) [48] Lara Medina et al. (2012) [50] Gauthier et al. (2010) [21] Rudnicka et al. (2007) [10] Yu et al. (2001) [52]
14
32–65 (mean 48)
29% HER2+, 29% triple negative
Unknown
Mean 8 years until Dx of brain metastasis
IT liposomal cytarabine, LRT, IV
Mean 10 months
N/A
N/A
CR 7%, PR 14%, SD 36%, PD 29%
61 (49 with breast cancer) 91
23–63 (mean 42.4)
20% ER+, 27% PRec+, 39% triple negative
20% HER2+
N/A
IT MTX, LRT, IVC
Mean 7 weeks
N/A
N/A
N/A
30–78 (median 53)
10% HER2+
Mean 4.5 months
N/A
25% at 1 year
59% PR, 13% CR
27–75 (median 49)
Range 0– 23.4 years (median 7.4 years) Median 27 months
IT MTX, hydrocortisone, oral folinic acid
67
70% ER+, 44% PRec+, 74% ER and/or PRec+, 21% triple negative 55% ER/PRec+
ITC for 85%, IVC for 61%, WBRT for 49%, LRT to 15%; 40% had 3 treatment methods
Median 16 weeks, mean 29 weeks
N/A
22% at 6 months; 7% at 1 year
N/A
8
32–62 (median 51.5)
25% ER+
Unknown
50% IT MTX and/or adoptive immunotherapy, 100% WBRT
Mean 123 days
N/A
N/A
37.5% SD, 55.6% PR
Fizazi et al. (1996) [12]
68
Mean 52
39% ER+, 31% PRec+
Unknown
High dose IT MTX + IM FA VS
Mean 14 weeks vs 7 weeks; median 67 days for all
N/A
N/A
Mean 77 days
N/A
N/A
High dose MTX+FA: 41% PR, 34% SD, 25% PD Low dose MTX: 14% PR, 48% SD, 38% PD N/A
Mean 12 weeks in ITC group (44 patients)
N/A
N/A
Unknown
Range 6– 128 months (median 17.5 months) Mean 66 months
Low dose IT MTX
Jayson et al. (1994) [9]
35
31–61 (median 45)
Unknown
Unknown
Mean 10.9 months
Boogerd et al. (1991) [5]
58
31–75 (median 57)
39% ER+, 20% ER , 41% unknown
Unknown
N/A
IT MTX in 11, IV MTX in 10, IV other chemotherapy in 5, no treatment in 3 IT MTX twice a week
In ITC group: 50% PR or CR, 50% PD
a According to the Response Evaluation Criteria In Solid Tumors. b/w = between, CR = complete response, Dx = diagnosis, ER = estrogen receptor, FA = folinic acid, HER = human epithelial receptor, IM = intramuscular, IT = intrathecal, ITC = intrathecal chemotherapy, IV = intravenous, IVC = intravenous (systemic) chemotherapy, LM = leptomeningeal metastasis, LRT = local radiation therapy, MTX = methotrexate, N/A = not available, PD = progressive disease, PRec = progesterone receptor, PR = partial response, SD = stable disease, vs = versus, WBRT = whole brain radiation therapy.
M. Kak et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022
Table 2 Breast cancer therapeutic case reports and retrospective studies with more than four patients reported in the literature
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However, a case report of two patients who received intravenous docetaxel in combination with carboplatinum resulted in clinical and radiographic improvement [44]. Taxane derivatives targeted toward lipoprotein receptor-related protein (LRP-1) to facilitate crossing of the BBB are currently under investigation in breast cancer brain metastases (NCT 02048059). If proven to be efficacious in brain metastases, further investigation in LM would be warranted. 4.3. Intrathecal therapy Intrathecal chemotherapy has served as a means to circumvent the BBB and blood–CSF barriers in LM. Four agents are currently approved by the United States FDA for direct injection into the intrathecal space: methotrexate, cytosine arabinoside, liposomal cytarabine arabinoside, and thiotepa. These agents have been directly evaluated [4,5,45,46], studied in combination with each other or other drugs [2,4,47–52] and studied using different doses and schedules [12,53]. Additionally, although not specifically FDA approved for this indication, trastuzumab and topotecan administered intrathecally have been evaluated in breast cancer LM [54– 58]. Three breast cancer specific trials of intrathecal regimens for LM reveal median OS of 2–4.5 months. Each employed a different intrathecal chemotherapy regimen. Responses were modest although complete response was noted in some patients, as defined by conversion of CSF cytology from positive to negative as well as absence of neurologic symptom progression [47,53,59] (Table 1). To our knowledge only one randomized trial exists comparing an intrathecal containing chemotherapy regimen to one without intrathecal chemotherapy in this patient population. This small study used predominantly methotrexate and demonstrated a trend toward better outcome without the use of intrathecal chemotherapy. Neurologic complications were higher in the patient group receiving intrathecal treatment [59]. That being said, there are numerous retrospective studies suggesting improved outcomes in patients receiving multi-modality treatment regimens which include intrathecal methotrexate [5,12,21,49,50,52,57], cytarabine [46,48,54,56], topotecan [54], thiotepa [57], and trastuzumab chemotherapy [48,55–58]. Similar OS and response rates have been noted in these retrospective studies, which are limited by selection bias. At the time of writing there is no evidence demonstrating obvious superiority of one intrathecally administered agent over others, in part secondary to a lack of uniform implementation of response criteria across studies [60]. Intrathecal administration of chemotherapy can be performed either via a ventricular catheter or lumbar puncture. Some evidence suggests route of delivery affects differences in outcome. It has been postulated that the potential complications from an indwelling reservoir are offset by the improved delivery of chemotherapy. This may be of particular importance for agents with shorter CSF half-lives necessitating frequent dosing [61]. One study of breast cancer patients with LM compared intralumbar and intraventricular administration, finding that treatment via the intraventricular route had an improved OS [62]. Intraventricular administration is currently the preferred method based on the USA National Comprehensive Cancer Network (NCCN) guidelines. NCCN guidelines also encourage CSF flow studies documenting unobstructed flow prior to administration to preserve efficacy and limit toxicity related to inadequate distribution. 5. Future directions Treatment of LM to date has been empiric, and not tailored to particular tumor types or tumor characteristics. Tailoring approaches toward specific tumor characteristics may prove beneficial for select subsets of patients. As an example, HER2 positive
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tumors have been shown to disproportionately metastasize to the CNS, likely because the BBB creates a ‘‘sanctuary site’’ from large therapeutic molecules such as trastuzumab. It is uncertain, but probable, that many newer HER2 targeted antibody or antibody-conjugates may face similar difficulty entering the CSF. Two distinct techniques have been employed to circumvent this barrier. The first is direct administration of trastuzumab into the CSF space. We await the results of ongoing studies (NCT01325207, NCT01373710) to further elucidate the role of this treatment modality. The second technique involves using novel agents which more readily cross the BBB. Attempts at this have been made in breast cancer brain metastases with the use of lapatinib in conjunction with cytotoxic chemotherapies. While the efficacy of results has been somewhat disappointing, it is possible that this concept of employing novel new agents may prove to be a viable treatment for breast cancer LM. Another such approach is the use of agents which bind to ligands, such as glutathione or LRP-1, which facilitate the transfer of molecules across the BBB. Presumably this may also allow the transfer of those molecules into the CSF to treat LM. A glutathione pegylated liposomal formulation of doxorubicin, and anthracycline with activity in breast cancer, are currently being investigated in a phase II trial for patients with breast cancer LM (NCT01818713). If this concept proves viable with regards to efficacy and acceptable toxicity, agents that have notably improved survival in extra-CNS breast cancer may be able to achieve therapeutic concentration in the CNS. In turn, this would hopefully lead to improvement in OS in breast cancer LM as well. 6. Conclusions We reviewed the diagnosis, prognosis, and various therapeutic managements for breast cancer LM. Prognosis for LM is poor; however, patients with breast cancer appear to have better outcomes when compared to patients with LM due to other solid tumors. Our understanding of prognostic factors in breast cancer LM is limited, with performance status being the most consistently significant variable. No definitive management paradigm exists for breast cancer LM patients and multiple treatment modalities are employed. Ultimately, there is no obvious optimal treatment regimen, although there are many reasonable options. There is the potential for substantial advances in the management of this aggressive disease. Some of these advances may depend on improving our understanding of the management of breast cancer brain metastases. Others will be unique to the treatment of breast cancer LM. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Surveillance, Epidemiology, and End Results Program: Turning Cancer Data into Discovery. Page on SEER Stat Fact Sheets: Breast Cancer. Available from: http://seer.cancer.gov/statfacts/html/breast.html [accessed on Aug 24, 2014]. [2] Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–72. [3] Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin 2003;21:25–66. [4] Hitchins RN, Bell DR, Woods RL, et al. A prospective randomized trial of singleagent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 1987;5:1655–62. [5] Boogerd W, Hart AA, van der Sande JJ, et al. Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment. Cancer 1991;67:1685–95. [6] Lee YT. Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 1983;23:175–80.
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[36] Taskar KS, Rudraraju V, Mittapelli RK, et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res 2012;29:770–81. [37] Ekenel M, Hormigo AM, Peak S, et al. Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007;85:223–7. [38] Lin NU, Diéras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009;15:1452–9. [39] Lin NU, Eierman W, Greil R, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol 2011;105:613–20. [40] Lien EA, Wester K, Lonning PE, et al. Distribution of tamoxifen and metabolites into brain tissue and brain metastases in breast cancer patients. Br J Cancer 1991;63:641–5. [41] Boogerd W, Dorresteijn LD, van Der Sande JJ, et al. 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Review
Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities Manisha Kak a, Rita Nanda b, Erika E. Ramsdale c, Rimas V. Lukas a,⇑ a
University of Chicago, Department of Neurology, 5841 S. Maryland Avenue, MC 2030, Chicago, IL 60637, USA University of Chicago, Section of Hematology and Oncology, Chicago, IL, USA c University of Virginia, Division of Hematology and Oncology, Charlottesville, VA, USA b
a r t i c l e
i n f o
Article history: Received 12 October 2014 Accepted 17 October 2014 Available online xxxx Keywords: Breast cancer Carcinomatous meningitis Chemotherapy Intrathecal therapy Leptomeningeal carcinomatosis Radiotherapy
a b s t r a c t Leptomeningeal metastasis (LM) in breast cancer patients confers a uniformly poor prognosis and decreased quality of life. Treatment options are limited and often ineffective, due in large part to limitations imposed by the blood–brain barrier and the very aggressive nature of this disease. The majority of studies investigating the treatment of LM are not specific to site of origin. Conducting randomized, disease-specific clinical trials in LM is challenging, and much clinical outcomes data are based on case reports or retrospective case series. Multiple studies have suggested that chemo-radiotherapy is superior to either chemotherapy or radiation therapy alone. Attempts to overcome current obstacles in the treatment of breast cancer LM hold promise for the future. We review the epidemiology, diagnosis, and prognosis of LM in breast cancer, and discuss the treatment options currently available as well as those under investigation. Ó 2014 Elsevier Ltd. All rights reserved.
1. Epidemiology Breast cancer affects one in eight women. It is estimated that 230,000 women in the USA will be diagnosed with breast cancer in 2014 [1]. Leptomeningeal metastasis (LM) can complicate virtually any malignancy, and breast carcinoma is the most common solid tumor associated with it [2,3]. Estimates of the incidence of LM in breast cancer patients in clinical series range from 1–8% [4,5], with autopsy series revealing an incidence as high as 16% [6]. Triple-negative breast cancer appears to have a higher likelihood of LM [7], and a shorter interval between initial diagnosis and development of LM [8].
2. Diagnosis The clinical presentation of LM is highly variable, as any level of the neuro-axis may be affected. The gold standard for diagnosis of LM is demonstration of malignant cells in cerebrospinal fluid (CSF), although the false negative rate may be substantial and improved sensitivity may rely on repeated sampling of the CSF [2]. Several studies have examined the diagnostic usefulness of other CSF measurements with mixed results. Hypoglycorrhachia (<50% of LM) ⇑ Corresponding author. Tel.: +1 773 834 9026; fax: +1 773 702 7485. E-mail address: [email protected] (R.V. Lukas).
[2,4,5,9–11], lymphocytic pleocytosis (25–64% of LM), and elevated opening pressures (50% of LM) are non-specific, but raise suspicion for LM in the proper clinical setting [11]. Also non-specific, elevated CSF protein was more sensitive in some studies [11,12], correlating with the diagnosis in 60–90% of cases. Other CSF biomarkers investigated include lactate dehydrogenase, carcinoembryonic antigen, lactate, oligoclonal bands, B-glucuronidase, beta-2 microglobulins, vascular endothelial growth factor, and cancer antigen 15-3 [2,13,14–16], but are not routinely used due to similarly suboptimal sensitivity and specificity. Neuroradiologic criteria for the diagnosis of LM have played a growing role since the advent of MRI [17]. The characteristic finding on MRI is meningeal enhancement, best noted at the skull base between cerebellar folia, along cranial nerves, and around the spinal cord and nerve roots (Fig. 1). MRI findings are abnormal in 75–90% of patients with cytology-positive CSF [11,18]. One retrospective review of 187 LM patients showed that 53% of patients were diagnosed by imaging, 23% by cytology, and 24% by both [30]. Most experts agree that typical MRI findings in conjunction with a consistent clinical picture fulfill diagnostic criteria for LM [19].
3. Prognosis Unfortunately, outcomes for breast cancer patients with LM remain dismal: rates of response to therapy and overall survival
http://dx.doi.org/10.1016/j.jocn.2014.10.022 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022
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(A)
(B)
definitively been shown to correlate with outcomes [2,4,5,7,11,12]. Other potential prognostic factors include age [5,7,12], control of systemic disease [12], histological grade [11], presence of cranial neuropathies [5], presence of lung metastases [5,11], no response to systemic or intrathecal therapy [10], and number of prior chemotherapy regimens [10,11,21]. Evaluation of tumor tissue for the presence of estrogen receptors, progesterone receptors, and human epithelial receptor 2 (HER2) is standard practice in breast cancer as these are both prognostic and predictive markers influencing management. The importance of receptor status in breast cancer LM mirrors its importance in breast cancer in both systemic disease as well as brain metastases [22]. Some studies show that HER2+ LM has a better OS while triple-negative patients have poorer OS [20]. However, other studies suggest that patients with triple-negative disease may only appear to have worse outcomes because they have shorter time until diagnosis of LM [8]. Suggestion has been made for serial evaluation of receptor status on these cells to guide clinical management [23]. Median survival in patients with LM from solid tumors ranges from 6–8 weeks in untreated patients, and 8–30 weeks in treated patients. Early studies combining patients with various primary tumors suggested that those with LM and breast cancer primaries have a higher response to treatment (up to 60% improving or stabilizing with chemotherapy and/or radiation therapy) and longer median survivals than those with other primaries (7 months versus 8–30 weeks) [2,4,11,20,24]. 4. Treatment
(C)
Therapeutic trials for solid tumor LM are small and include heterogeneous patient populations. Accrual is challenging because of the relatively low incidence and rapidly progressive nature of the disease. The majority of data available on efficacy and outcomes are from non-randomized or observational studies in patients who were not uniformly treated and have a wide range of tumor types. Additionally, endpoints have varied between trials, making it challenging to determine the optimal management of patients with LM. Modalities used in patients with LM to date include radiation therapy (RT), systemic therapy, and intrathecal therapy. 4.1. RT
Fig. 1. (A) Sagittal T1-weighted post-contrast MRI of the brain revealing enhancing lesions deep within the sulci supratentorially (solid arrow), on the cerebellar surface (dashed arrow), and at the anterior surface of the fourth ventricle (dashed arrow). (B) Axial T1-weighted post-contrast MRI of the brain showing enhancing lesions on the cerebellar surfaces (arrow). (C) Sagittal T1-weighted post-contrast MRI of the lumbosacral spine revealing ‘‘sugar coating’’ of the surface of the spinal cord (solid arrow) and bulkier enhancement of the cauda equina (dashed arrow).
(OS) have not markedly changed, despite dramatic improvement in outcomes for those with visceral disease. Outside of performance status (PS), no consistent set of prognostic or predictive indicators have been elucidated to guide management. PS has demonstrated prognostic significance in a number of studies [7,10,11,20,21]. Pre-treatment CSF markers for prognostication have not
Craniospinal RT plays an important role in the treatment of central nervous system (CNS) metastases because it addresses the entire CSF space. However, it is often not used to treat LM due to significant toxicity, particularly in patients who may have overlapping RT fields from prior chest wall RT. A more focal approach is often employed to limit toxicity. Whole brain RT, alone or followed by chemotherapy, is used to treat a substantial portion of the CSF space, palliate symptoms, and improve quality of life [5,10]. Focal RT is frequently used to treat bulky disease as other treatment modalities may have limited effect on regions of large CSF tumor burden. Focal RT can be administered either in a fractionated manner or as a single dose via stereotactic radiosurgery. No broad guidelines exist and decisions are made on a case by case basis. In turn, it is unclear whether increased doses or alternate dosing schedules of radiation may be appropriate in certain tumor subtypes. Studies have suggested that tumors arising in patients with deleterious germline BRCA1/2 mutations are more sensitive to the DNA-damaging effects of RT [19]. There exists mixed data regarding the role of receptor status on sensitivity to RT. Triple negative patients with intracranial metastases (not LM specifically) have high objective response rates to RT but shorter OS [25]. Other studies have not demonstrated receptor status to be predictive of outcome to hypofractionated RT [26].
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4.2. Systemic therapies Delivery of systemically administered treatments into CSF in therapeutic concentrations is limited by the blood–brain barrier (BBB) and blood–CSF barriers. The barrier between the CNS and the rest of the body is a complicated and dynamic system limiting the ability of many molecules, particularly large hydrophilic ones, from reaching the CNS in therapeutic concentrations. Despite this, large non-lipophilic agents which would presumably inadequately cross the BBB have been show to lead to radiographic responses in the CNS [27]. Our understanding of which systemically delivered agents are able to readily treat CNS malignancies continues to evolve, influencing the way this patient population is managed. In the following section we will discuss treatment of LM focusing primarily on breast cancer-specific LM trials (Table 1) and breast cancer-specific larger case series (Table 2). HER2 has proven to be a viable target in patients with HER2amplified breast cancer, leading to the United States Food and Drug Administration (FDA) approval of anti-HER2 therapies in these patients. It does not appear that the use of HER2 targeted therapies decreases the rate of CNS involvement [28]. Eighteen to 30% of advanced breast cancer patients receiving trastuzumab-based therapy develop brain metastases, and 4–19% of them develop LM, often while their systemic tumor burden responds [29,30]. This may be because trastuzumab does not effectively cross the BBB, or because of loss of HER2 amplification in the breast cancer cells that metastasize to the brain. However, patients with HER2 amplified breast cancer and CNS metastases, both in brain parenchyma and CSF, fare better than those who are HER2 negative [20,22]. This may be due to more favorable natural history, better CNS response to therapies, better extra-CNS response to therapy, or a combination of these factors. The large size of antibodies/antibody-drug conjugates precludes them from easily entering the CNS. Trastuzumab, the first and best studied of the anti-HER2 antibodies, has low penetration through the BBB with 300-fold lower concentration in human CSF compared to serum [31]. Means of increasing the BBB permeability of trastuzumab have been investigated in animal models [32]. There have been no trials investigating the role of systemically administered trastuzumab in the treatment of LM specifically to our knowledge. Pertuzumab, another anti-HER2 antibody, and adotrastuzumab emtansine, an antibody-microtubule inhibitor conjugate, also have not been evaluated specifically in LM or brain metastases. It is unclear what the CNS concentrations of these agents are when delivered intravenously. However, numerous retrospective studies have suggested potential benefit of systemic chemotherapy on response rates and OS of breast cancer patients with CNS metastases and LM [12,33,34].
To circumvent the BBB, lapatinib, a HER2/epidermal growth factor receptor dual tyrosine kinase inhibitor, has been investigated. When first approved, it was thought to effectively cross the BBB, but recent animal studies have shown that it is not always distributed in high concentrations in brain metastases [35]. One study conducted in mice showed the concentration of lapatinib in brain metastases was 7-fold to 9-fold higher in brain metastases compared to surrounding brain tissue, but still only 10–20% of the concentration measured in peripheral metastases [35]. Lapatinib has been shown to be active in combination with capecitabine, a 5-fluorouracil prodrug whose metabolites cross the BBB, when used in patients with HER2 positive breast cancer previously treated with trastuzumab [36]. When lapatinib was studied as a single agent in patients with progressive brain metastases, the response rate was limited (2.6 to 6%) in this refractory patient population [37]. However, the addition of capecitabine after progression on lapatinib alone yielded objective responses in 20% of patients. In patients with newly diagnosed brain metastases objective responses were seen in one-third to two-thirds of patients. Similar responses were not noted when combining lapatinib with other agents such as topotecan in this patient population [38]. While to our knowledge this agent has not been studied prospectively in LM it has apparent efficacy in HER2 positive breast cancer patients with brain metastases, suggesting the potential for response in LM patients, although this requires further study before being broadly applied. Literature on hormone antagonists and aromatase inhibitors in LM is sparse, and hormonal agents’ ability to penetrate the BBB has been minimally investigated thus far. Tamoxifen, an estrogen receptor antagonist, is a highly lipophilic agent that can cross the BBB and has enhanced ability to do so when metastases increase permeability. Significant and even cytotoxic concentrations of tamoxifen have been observed in brain tissue, and higher concentrations in brain tumor tissue [39]. Furthermore, prolonged progression free survival has been seen in anecdotal reports of breast cancer LM patients treated with various therapies targeted towards hormone receptors [40]. Temozolomide, an alkylating agent approved for gliomas, has been evaluated in breast cancer brain metastases with response rates ranging from 0 to 44% in breast cancer patients receiving temozolomide alone or in combination with whole brain RT, with the highest rates reported with combined chemo-radiotherapy [41]. While cases of LM responses in other solid tumors have been reported [42], there are no prospective trials and no case reports or case series specifically looking at temozolomide in breast cancer LM to our knowledge. Taxane-based chemotherapies such as paclitaxel and docetaxel are antimicrotubular agents effective in metastatic breast cancer, but have been proven to lack adequate CNS penetration [43].
Table 1 Breast cancer specific leptomeningeal metastasis trials Study (year)
Phase Patients Age, years
Boogerd et al. 1 (2004) [59] Orlando et al. 1 (2002) [47]
1 Jaeckle et al. (2001) [53]
35 13
56
Mean 49.6 vs 57.9 Range 30–67 (median 45)
Receptor
Treatment Interval b/w initial Dx and development of LM
Unknown Unknown Unknown Unknown
Range 28–74 Unknown Unknown (median 50)
LRT + IVC vs LRT + ITC IT thiotepa, MTX, hydrocortisone, cytarabine, oral folinic acid IT liposomal cytarabine
Overall survival
Progression Progression Response ratea free survival free survival at 12 mo
Mean 30.3 weeks N/A vs 18.3 weeks Mean 63 days N/A (range 1–278 days)
Mean 88 days
49 days
N/A N/A
19%
59% PR or SD vs 67% PR or SD 100% had SD or PD (no clinical response observed in any patients) 28% PR or CR
a According to the Response Evaluation Criteria In Solid Tumors. b/w = between, CR = complete response, Dx = diagnosis, IT = intrathecal, ITC = intrathecal chemotherapy, IVC = intravenous (systemic) chemotherapy, LM = leptomeningeal metastasis, LRT = local radiation therapy, MTX = methotrexate, N/A = not available, PR = partial response, PD = progressive disease, SD = stable disease, vs = versus, WBRT = whole brain radiation therapy.
Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022
4
Study (year)
Patients
Age range, years
Receptor
HER status
Interval b/w initial Dx and development of LM
Treatment
Overall survival
Progression free survival
Progression free survival % in time
Relative responsea
Chmielowska et al. (2012) [48] Lara Medina et al. (2012) [50] Gauthier et al. (2010) [21] Rudnicka et al. (2007) [10] Yu et al. (2001) [52]
14
32–65 (mean 48)
29% HER2+, 29% triple negative
Unknown
Mean 8 years until Dx of brain metastasis
IT liposomal cytarabine, LRT, IV
Mean 10 months
N/A
N/A
CR 7%, PR 14%, SD 36%, PD 29%
61 (49 with breast cancer) 91
23–63 (mean 42.4)
20% ER+, 27% PRec+, 39% triple negative
20% HER2+
N/A
IT MTX, LRT, IVC
Mean 7 weeks
N/A
N/A
N/A
30–78 (median 53)
10% HER2+
Mean 4.5 months
N/A
25% at 1 year
59% PR, 13% CR
27–75 (median 49)
Range 0– 23.4 years (median 7.4 years) Median 27 months
IT MTX, hydrocortisone, oral folinic acid
67
70% ER+, 44% PRec+, 74% ER and/or PRec+, 21% triple negative 55% ER/PRec+
ITC for 85%, IVC for 61%, WBRT for 49%, LRT to 15%; 40% had 3 treatment methods
Median 16 weeks, mean 29 weeks
N/A
22% at 6 months; 7% at 1 year
N/A
8
32–62 (median 51.5)
25% ER+
Unknown
50% IT MTX and/or adoptive immunotherapy, 100% WBRT
Mean 123 days
N/A
N/A
37.5% SD, 55.6% PR
Fizazi et al. (1996) [12]
68
Mean 52
39% ER+, 31% PRec+
Unknown
High dose IT MTX + IM FA VS
Mean 14 weeks vs 7 weeks; median 67 days for all
N/A
N/A
Mean 77 days
N/A
N/A
High dose MTX+FA: 41% PR, 34% SD, 25% PD Low dose MTX: 14% PR, 48% SD, 38% PD N/A
Mean 12 weeks in ITC group (44 patients)
N/A
N/A
Unknown
Range 6– 128 months (median 17.5 months) Mean 66 months
Low dose IT MTX
Jayson et al. (1994) [9]
35
31–61 (median 45)
Unknown
Unknown
Mean 10.9 months
Boogerd et al. (1991) [5]
58
31–75 (median 57)
39% ER+, 20% ER , 41% unknown
Unknown
N/A
IT MTX in 11, IV MTX in 10, IV other chemotherapy in 5, no treatment in 3 IT MTX twice a week
In ITC group: 50% PR or CR, 50% PD
a According to the Response Evaluation Criteria In Solid Tumors. b/w = between, CR = complete response, Dx = diagnosis, ER = estrogen receptor, FA = folinic acid, HER = human epithelial receptor, IM = intramuscular, IT = intrathecal, ITC = intrathecal chemotherapy, IV = intravenous, IVC = intravenous (systemic) chemotherapy, LM = leptomeningeal metastasis, LRT = local radiation therapy, MTX = methotrexate, N/A = not available, PD = progressive disease, PRec = progesterone receptor, PR = partial response, SD = stable disease, vs = versus, WBRT = whole brain radiation therapy.
M. Kak et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
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Table 2 Breast cancer therapeutic case reports and retrospective studies with more than four patients reported in the literature
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However, a case report of two patients who received intravenous docetaxel in combination with carboplatinum resulted in clinical and radiographic improvement [44]. Taxane derivatives targeted toward lipoprotein receptor-related protein (LRP-1) to facilitate crossing of the BBB are currently under investigation in breast cancer brain metastases (NCT 02048059). If proven to be efficacious in brain metastases, further investigation in LM would be warranted. 4.3. Intrathecal therapy Intrathecal chemotherapy has served as a means to circumvent the BBB and blood–CSF barriers in LM. Four agents are currently approved by the United States FDA for direct injection into the intrathecal space: methotrexate, cytosine arabinoside, liposomal cytarabine arabinoside, and thiotepa. These agents have been directly evaluated [4,5,45,46], studied in combination with each other or other drugs [2,4,47–52] and studied using different doses and schedules [12,53]. Additionally, although not specifically FDA approved for this indication, trastuzumab and topotecan administered intrathecally have been evaluated in breast cancer LM [54– 58]. Three breast cancer specific trials of intrathecal regimens for LM reveal median OS of 2–4.5 months. Each employed a different intrathecal chemotherapy regimen. Responses were modest although complete response was noted in some patients, as defined by conversion of CSF cytology from positive to negative as well as absence of neurologic symptom progression [47,53,59] (Table 1). To our knowledge only one randomized trial exists comparing an intrathecal containing chemotherapy regimen to one without intrathecal chemotherapy in this patient population. This small study used predominantly methotrexate and demonstrated a trend toward better outcome without the use of intrathecal chemotherapy. Neurologic complications were higher in the patient group receiving intrathecal treatment [59]. That being said, there are numerous retrospective studies suggesting improved outcomes in patients receiving multi-modality treatment regimens which include intrathecal methotrexate [5,12,21,49,50,52,57], cytarabine [46,48,54,56], topotecan [54], thiotepa [57], and trastuzumab chemotherapy [48,55–58]. Similar OS and response rates have been noted in these retrospective studies, which are limited by selection bias. At the time of writing there is no evidence demonstrating obvious superiority of one intrathecally administered agent over others, in part secondary to a lack of uniform implementation of response criteria across studies [60]. Intrathecal administration of chemotherapy can be performed either via a ventricular catheter or lumbar puncture. Some evidence suggests route of delivery affects differences in outcome. It has been postulated that the potential complications from an indwelling reservoir are offset by the improved delivery of chemotherapy. This may be of particular importance for agents with shorter CSF half-lives necessitating frequent dosing [61]. One study of breast cancer patients with LM compared intralumbar and intraventricular administration, finding that treatment via the intraventricular route had an improved OS [62]. Intraventricular administration is currently the preferred method based on the USA National Comprehensive Cancer Network (NCCN) guidelines. NCCN guidelines also encourage CSF flow studies documenting unobstructed flow prior to administration to preserve efficacy and limit toxicity related to inadequate distribution. 5. Future directions Treatment of LM to date has been empiric, and not tailored to particular tumor types or tumor characteristics. Tailoring approaches toward specific tumor characteristics may prove beneficial for select subsets of patients. As an example, HER2 positive
5
tumors have been shown to disproportionately metastasize to the CNS, likely because the BBB creates a ‘‘sanctuary site’’ from large therapeutic molecules such as trastuzumab. It is uncertain, but probable, that many newer HER2 targeted antibody or antibody-conjugates may face similar difficulty entering the CSF. Two distinct techniques have been employed to circumvent this barrier. The first is direct administration of trastuzumab into the CSF space. We await the results of ongoing studies (NCT01325207, NCT01373710) to further elucidate the role of this treatment modality. The second technique involves using novel agents which more readily cross the BBB. Attempts at this have been made in breast cancer brain metastases with the use of lapatinib in conjunction with cytotoxic chemotherapies. While the efficacy of results has been somewhat disappointing, it is possible that this concept of employing novel new agents may prove to be a viable treatment for breast cancer LM. Another such approach is the use of agents which bind to ligands, such as glutathione or LRP-1, which facilitate the transfer of molecules across the BBB. Presumably this may also allow the transfer of those molecules into the CSF to treat LM. A glutathione pegylated liposomal formulation of doxorubicin, and anthracycline with activity in breast cancer, are currently being investigated in a phase II trial for patients with breast cancer LM (NCT01818713). If this concept proves viable with regards to efficacy and acceptable toxicity, agents that have notably improved survival in extra-CNS breast cancer may be able to achieve therapeutic concentration in the CNS. In turn, this would hopefully lead to improvement in OS in breast cancer LM as well. 6. Conclusions We reviewed the diagnosis, prognosis, and various therapeutic managements for breast cancer LM. Prognosis for LM is poor; however, patients with breast cancer appear to have better outcomes when compared to patients with LM due to other solid tumors. Our understanding of prognostic factors in breast cancer LM is limited, with performance status being the most consistently significant variable. No definitive management paradigm exists for breast cancer LM patients and multiple treatment modalities are employed. Ultimately, there is no obvious optimal treatment regimen, although there are many reasonable options. There is the potential for substantial advances in the management of this aggressive disease. Some of these advances may depend on improving our understanding of the management of breast cancer brain metastases. Others will be unique to the treatment of breast cancer LM. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Surveillance, Epidemiology, and End Results Program: Turning Cancer Data into Discovery. Page on SEER Stat Fact Sheets: Breast Cancer. Available from: http://seer.cancer.gov/statfacts/html/breast.html [accessed on Aug 24, 2014]. [2] Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–72. [3] Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin 2003;21:25–66. [4] Hitchins RN, Bell DR, Woods RL, et al. A prospective randomized trial of singleagent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 1987;5:1655–62. [5] Boogerd W, Hart AA, van der Sande JJ, et al. Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment. Cancer 1991;67:1685–95. [6] Lee YT. Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 1983;23:175–80.
Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022
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Please cite this article in press as: Kak M et al. Treatment of leptomeningeal carcinomatosis: Current challenges and future opportunities. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2014.10.022