Leptomeningeal metastasis from solid tumors

Journal of the Neurological Sciences 411 (2020) 116706

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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns

Review Article

Leptomeningeal metastasis from solid tumors Jigisha P. Thakkar

a,b

, Priya Kumthekar

c,d,f

c,d

c,d,e,f

, Karan S. Dixit , Roger Stupp

, Rimas V. Lukas

c,d,⁎

T

a

Loyola University Medical Center, Department of Neurology, United States of America Department of Neurosurgery, United States of America Northwestern University, Department of Neurology, United States of America d Lou & Jean Malnati Brain Tumor institute of the Robert H. Lurie Comprehensive Cancer Center, United States of America e Department of Neurological Surgery, United States of America f Division of Hematology/Oncology, United States of America b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Leptomeningeal metastases Intrathecal chemotherapy Central nervous system metastases Cerebrospinal fluid Carcinomatous meningitis

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges (pia, subarachnoid space and arachnoid mater), and dura. Leptomeningeal metastases (LM), also known by different terms including neoplastic meningitis and carcinomatous meningitis, occur in both solid tumors and hematologic malignancies. This review will focus exclusively on LM arising from solid tumors with a goal of providing the reader an understanding of the epidemiology, pathophysiology, clinical presentation, prognostication, current management and future directions.

1. Epidemiology

2. Pathophysiology

The incidence of LM from solid tumors is difficult to estimate and not clearly defined as this information is not tracked at the population level. Autopsy studies including single institution series lend some insight. However, these represent end-state disease and may not reflect a clinically relevant incidence of LM [1]. It is hypothesized that the incidence and prevalence of LM diagnoses may be increasing due to a combination of factors including improved imaging techniques, a lower threshold for initiating diagnostic work-up, as well as improved systemic control and prolonged survival in patients with systemic malignancies. LM can occur with nearly every malignancy, however, the highest incidence of LM appears to be in melanoma (23%) and lung cancer (9–25%) then followed by breast cancer (5%) [2–4]. Median time from systemic cancer diagnosis to the diagnosis of LM is approximately 1–2 years [5,6]. Patients with hormone receptor positive breast cancer have the longest interval between initial cancer diagnosis and development of LM [7]. Concurrent systemic disease progression is seen in up to 60–70% of patients with LM and almost 60% will have associated parenchymal brain involvement [5,8]. This means that the treating clinician will need to take into account the management of extra-CNS disease as well as parenchymal CNS disease in a substantial majority of patients.

Much of what is thought regarding the pathophysiology of LM remains speculative and not systematically studied. LM spread may occur via multiple routes: hematogenous, direct infiltration from metastatic brain lesions, or via an endoneural/perineural and perivascular route [9]. Another mechanism of LM spread is iatrogenic seeding of cerebrospinal fluid (CSF). Patients who undergo piecemeal resection, particularly of posterior fossa metastases, are at a higher risk of developing LM than those who undergo en bloc resection [10,11]. Similar to the pathophysiology of brain metastases it is likely a multistep biological process which leads to LM [12]. Tumor cells must leave the primary tumor, travel through the vasculature and then reach a location in which they can traverse into the CSF. This may most likely occur via the partially fenestrated vasculature of the choroid plexus. Once within the CSF there are likely specific factors which may help facilitate tumor cell growth and proliferation in accord with the “seed and soil” hypothesis [12]. Within the CSF, tumor cells are relatively protected from the immune surveillance and an intact BCSFB (blood–CSF barrier) [13]. This may contribute to the facilitation of their malignant cell survival even in the midst of effective systemic therapy of extra-CNS cancer, a phenomenon often referred to as the CSF sanctuary.

⁎

Corresponding author at: 710 N. Lake Shore Drive, Abbott Hall 1114, Chicago, IL 60611, United States of America. E-mail address: [email protected] (R.V. Lukas).

https://doi.org/10.1016/j.jns.2020.116706 Received 2 October 2019; Received in revised form 17 January 2020; Accepted 22 January 2020 Available online 23 January 2020 0022-510X/ © 2020 Elsevier B.V. All rights reserved.

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Table 1 Symptom localization and management of leptomeningeal metastases. Symptom

Etiology and neuroaxis location

Management

High ICP symptoms: morning headache worse on lying down, nausea, unsteadiness of gait

Cerebral Communicating hydrocephalus Non communicating hydrocephalus

Seizures

Cerebral

Facial droop, dysarthria Dysphagia, hearing loss, diplopia, tongue deviation, trigeminal neuralgia, facial muscle weakness Allodynia, hyperesthesia Hypoesthesia Urine and fecal incontinence, saddle anesthesia, constipation

Cranial nerves

Steroidsa WBRT or VP shunt placement Focal Radiation Acetazolamide Broad Spectrum non-enzyme inducing anti-epileptic drugs Steroids Focal RT Supportive measures Gabapentin, pregabalin, duloxetine, amitriptyline. No treatment needed Focal radiation Supportive measures Steroids Focal radiation Steroids Focal radiation

Spinal nerves Cauda Equina

Radicular pain

Nerve roots

Weakness

Spinal nerves

Abbreviations: WBRT-Whole Brain Radiation Therapy, VP-ventriculo-peritoneal a Steroid of choice is dexamethasone as it has low mineralocorticoid activity. Our institutional preference is once a day dosing with minimal effective dose and duration.

3. Clinical features

neuroanatomic localization, non-localizable symptoms related to an elevation in intracranial pressure (ICP) can also be seen with LM. Infiltration of leptomeninges with cancer cells and/or the associated inflammation may also cause an impedance of the normal CSF outflow via the arachnoid granulations which leads to increased ICP with or without communicating/non-obstructive hydrocephalus [9]. It is uncommon for LM to cause an obstructive hydrocephalus. This is more often encountered in the setting of brain metastases. Common manifestations of increased ICP include headaches which are more pronounced when lying down and upon first awakening, ataxia, cognitive slowing, urinary incontinence, vision decline, nausea, vomiting, horizontal diplopia (a “false” localizing sign leading to abducens nerve (cranial nerve VI) compression at the base of the skull due to increased ICP), and somnolence.

Signs and symptoms associated with LM are generalized but may be localizable with a careful neurological exam. As LM may affect any part of the neuro-axis a panoply of symptoms may be present (Table 1). A high index of suspicion for LM is advisable in any cancer patient with neurologic symptoms, however, taking care to differentiate them from those caused by those due to brain metastases, systemic involvement of cancer, or neurologic symptoms of cancer treatment. As the CSF bathes the entire CNS, LM may manifest with non-contiguous lesions which upends the Occam's Razor concept of attempting to localize neurologic signs and symptoms to a single lesion. Expectedly, localizable symptoms depend on the neuroanatomy involved and are presumably caused predominantly by infiltrative involvement. The nerves exiting the brain [cranial nerves (CN)] or the spinal cord (spinal nerve roots, cauda equina) are prone to clinically apparent involvement. Tumor cells invade spinal and cranial nerves at first producing demyelination and finally destroying the axons of those nerves [5]. Cranial neuropathies can cause expected symptomatology: diplopia, ptosis, facial pain or numbness, facial palsy, tinnitus, hearing loss, vertigo, dysarthria, and dysphagia. Multiple cranial nerve deficits can suggest a pathologic process in the subarachnoid space. In addition, irritation/infiltration of the cerebral cortex may manifest with focal symptoms based on the involved anatomic structures. These can manifest as positive symptoms such as seizures or negative symptoms such as an impairment or loss of function. Invasion, compression, or spasm of blood vessels located on the brain convexity or in the Virchow-Robin spaces may cause ischemia leading to transient attacks, strokes, and encephalopathy secondary to a global decrease in cerebral blood flow [14]. In addition to cranial symptomatology, patients may develop signs or symptoms localizable to the spinal cord. The ventral root containing the motor axons and the dorsal root containing the sensory axons exit the spinal cord into the subarachnoid space to form the spinal nerve. Spinal nerves then enter the neural foramen and exits the vertebral column. Infiltration of the nerve roots and spinal nerves causes motor and/or sensory symptoms. These manifest as flaccid weakness, hypoesthesia, paresthesia, and radicular pain. Involvement of the most caudal spinal nerve roots can result in a cauda equina syndrome (saddle anesthesia, urinary incontinence, fecal incontinence and constipation from of parasympathetic denervation of the rectum and sigmoid and anal sphincters) [5,15]. While the above described clinical findings relate to specific

4. Diagnosis Diagnosis is formally established based on a positive (malignant) CSF cytology, radiologic (nodular CT or MRI alterations) with corresponding clinical findings, and/or signs and symptoms suggestive of CSF involvement in a patient with known malignancy [16]. While positive CSF cytology provides the highest level of certainty in the diagnosis of LM it is not essential for initiating treatment of LM if the remainder of the diagnostic evaluation is supportive of LM. Work up of LM includes: central nervous system (CNS) imaging with MRI brain and entire spine with and without contrast (CT if MRI is not feasible), CSF analysis (ideally, but not essentially, performed after MRI to prevent false positive sign of dural enhancement) and systemic imaging, staging/restaging with CT and/or PET. Experienced neuro-oncologists and neuro radiologists are often comfortable in differentiating between pachymeningeal (dural) enhancement which can be seen post-lumbar puncture and leptomeningeal enhancement. When performing a lumbar puncture there is value in assessing the opening pressure. If elevated treatment of this can lead to rapid symptomatic improvement. Medical management can include simple maneuvers such as elevating the head of bed during sleep as well as the use of acetazolamide to decrease the production of CSF. Surgical management via an extraventricular drain in the acute setting and a ventriculoperitoneal shunt for longer term control can be considered. The concerns regarding extra-CNS seeding of tumor are usually outweighed by concerns regarding increased ICP and the morbidity/mortality associated with LM itself. Efforts are ongoing to standardize diagnostic workup and interpretation coordinated by the Response Assessment in Neuro-Oncology 2

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Fig. 1. MRI Brain and spine with gadolinium contrast demonstrating bulky nodular leptomeningeal metastases. A: MRI brain T1 post contrast axial view demonstrating bulky enhancement of the cerebellar folia. B: MRI brain T1 post contrast axial view demonstrating diffuse bulky enhancement of the cerebral sulci. C: MRI C-spine T1 post contrast sagittal view demonstrating multiple nodular foci of enhancement along the cervical cord leptomeninges. D: MRI L spine T1 post contrast sagittal view demonstrating multiple nodular foci of enhancement along the lumbar cord and cauda equina leptomeninges.

Flow cytometry and DNA single-cell cytometry are two techniques that measure the chromosomal content of cells. This is 2–3 times more sensitive than cytology for the detection of hematologic malignancy cells in the CSF [21,22]. Epithelial cell adhesion molecule (EpCAM) is expressed by solid tumors of epithelial origin like non-small-cell lung cancer, breast cancer or ovarian cancer. EpCAM-based flow cytometry assay is superior to CSF cytology for the diagnosis of LM in patients with epithelial tumors [23]. A number of other potential CSF biomarkers have been investigated both for the diagnosis as well as monitoring of LM. These include beta-glucoronidase, carcinoembryonic antigen, CA 15–3, and vascular endothelial growth factor, amongst others [24,25]. While many of these have demonstrated promise in small studies, none have been established as a component of the standard evaluation of all LM or suspected LM patients. A very promising area of research is the utilization of circulating tumor DNA (ctDNA) in the CSF as a complementary tool for the diagnosis and characterization of LM. It can also serve as a means to detect actionable genomic alterations and monitor responses to therapy in patients with LM [101]. CSF ctDNA has been utilized in the evaluation of patients with primary brain tumors, brain metastases, and LM [26,27]. Knowledge from one histology and from one anatomic space (brain parenchyma vs CSF) will help inform our understanding of the value of this technique in the other. In LM the role of CSF ctDNA has been best studied in lung cancer where it has demonstrated excellent sensitivity for detecting resistance mutations to targeted therapies in a minimally invasive fashion [28].

(RANO) group and its Leptomeningeal Assessment in Neuro-Oncology (LANO) scorecard as well as the European Association of NeuroOncology- European Society of Medical Oncology (EANO-ESMO) group [17,18]. Neither of these two systems has yet been validated. These groups use clinical symptoms, imaging and CSF analysis for diagnosis and assessment of treatment response. They enlist symptoms that should alert the physician for LM (headache, nausea, vomiting, mental changes, gait difficulty, cranial nerve palsy, sensory-motor deficits, cauda equina syndrome and radicular pain) as well as recommend a scoring system that takes into account exam domains (level of consciousness, behavior, gait, strength, sensation, eye movements, facial strength, hearing and swallowing) to assess for progression [17,18]. 4.1. CSF Cytological evaluation of the CSF is the gold standard for diagnosing LM and helps assess treatment response [9]. CSF sampling should ideally include measurement of the opening pressure (as mentioned above), cell count with differential, protein, glucose, and cytologic examination [13]. A substantial volume (> 10 mL) is generally recommended for CSF cytology as with higher volume likelihood of capturing malignant cells increases [19]. Delays in CSF processing results in a decrease of tumor cell viability and diagnostic yield, thus immediate transport to and processing by the cytology lab is important. For example, it has been demonstrated that after 90 min only 10% of normal lymphocytes remain [20]. As it is unknown what the decrease in yield of neoplastic solid tumor cells is in ex vivo CSF it should be processed promptly to reduce potential cell death/lysis. Indirect and non-specific indicators of CSF involvement include elevated opening pressure (> 20 cm H2O), elevated protein (> 45 mg/dL), decreased glucose (50–60 mg/dL), and elevated white blood cell count (> 4/ mm3, most often lymphocytes) [5,17]. Cytology sensitivity for malignant cells has been reported 40 years ago as 45% with a single lumbar puncture (LP) and 90% with a third LP [5]. It is uncertain if this still holds true in the contemporary era. The overlapping LANO and EANO-ESMO [17,18] recommendations for CSF analysis include obtaining ideally > 10 mL of CSF, processing within 30 mins and avoiding hemorrhagic contamination. If first sample is negative then second analysis should be done to improve sensitivity. A positive response is considered when cytology converts from positive to negative from same site and is maintained for a period of 4 weeks. Progressive disease is defined by conversion of negative to positive cytology or persistent positive cytology.

4.2. Imaging Gadolinium enhanced MRI brain and spine is the gold standard imaging modality to diagnose LM, in patients with supportive clinical findings it has a sensitivity of 76% and specificity of 77% [29]. The combined LANO and EANO-ESMO recommendation for imaging includes obtaining MRI brain and spine with and without contrast, volumetric 3DT1 (magnetization-prepared rapid acquisition with gradient echo) with slice thickness < 1 mm in 3 planes (axial, coronal and sagittal) [17,18]. Assess for nodular (Fig. 1) versus liner (Fig. 2) enhancement, focal versus diffuse disease and presence of hydrocephalus. Nodular disease is defined as enhancing nodules > 5X10mm in orthogonal diameter. Response assessment is scored from +3 to −3 based on improvement, resolution, worsening or new area of metastases. The most frequent MRI findings include focal or diffuse enhancement of leptomeninges along the sulci, cranial nerves and spinal nerve roots, 3

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Fig. 2. MRI Brain and spine with gadolinium contrast demonstrating non-bulky liner leptomeningeal metastases. A: MRI C and T spine T1 post contrast sagittal view demonstrating linear enhancement along the cervical and thoracic cord leptomeninges. B: MRI brain T1 post contrast axial view demonstrating diffuse linear enhancement of the cerebral sulci.

Fig. 3. CT head and spine with contrast demonstrating diffuse leptomeningeal enhancement. A: CT head axial view with contrast demonstrating diffuse leptomeningeal enhancement along the in the cerebral sulci. B: CT head axial view with contrast demonstrating diffuse leptomeningeal enhancement along cerebellar folia. C: CT lumber spine sagittal view with contrast demonstrating linear leptomeningeal enhancement along the lumbar leptomeninges.

therapy.

linear or nodular enhancement of the cord and thickening of lumbosacral roots. If MRI is contraindicated, then CT brain and spine with contrast (Fig. 3) can be used although it is viewed as a less sensitive imaging modality. CSF flow studies can be performed to evaluate the patency of the CSF pathway in cases where intrathecal (also called intra-CSF or intraventricular) chemotherapy is considered in setting of suspicion of obstruction to CSF outflow. Abnormal CSF flow interferes with uniform distribution of intra-CSF chemotherapy and can lead to toxicity due to excess accumulation of chemotherapy [30]. Cisternogram involves injection of a radionuclide tracer such as Indium-111 DTPA or Technetium-99 m into the CSF which can demonstrate focal areas of obstructive hydrocephalus. Cisternogram can help assess CSF flow before intra-CSF therapy is initiated. CSF flow studies should be done via the same route as the planned route of administration of intrathecal (IT) drug to assess drug distribution. Hence Ommaya reservoir should be placed before examining CSF flow dynamics. Of note, bulky LM on imaging is almost always associated with poor CSF flow, and thus one can assume poor flow when bulky tumor is seen on imaging. This can help guide the therapeutic decision making either by prior determining a patient is not an optimal candidate for IT treatment or by the use of radiation to treat the bulky disease prior to moving forward with IT

5. Prognosis A diagnosis of LM carries a poor prognosis with an estimated median survival of only 2–4 months despite therapy, and 4–6 weeks if untreated [31–37]. Favorable prognostic factors (low risk disease) includes good performance status, minor neurologic deficits, low CSF protein (< 50 mg/dL), minimal or well controlled systemic disease and treatment-responsive histologies with remaining treatment options [7,38–40]. Poor prognostic factors (high risk disease) include a KPS < 60, severe neurologic deficits, extensive systemic disease with few treatment options, bulky CNS disease, and encephalopathy [2,16]. 6. Clinical management Management goals of LM include improving patient's neurologic function, quality of life, preventing further neurologic deterioration and prolonging survival. Treatment of LM should be individualized based on a variety of aspects including prognostic factors, tumor histology, presence of bulky disease, and the state of the systemic disease (Fig. 4). In many cases, it may be reasonable to pursue a palliative and comfort 4

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Fig. 4. Management of Leptomeningeal disease. High risk: KPS < 60, severe neurologic deficits, extensive systemic disease with few treatment options, bulky CNS disease, and encephalopathy. Low risk: Good performance status, minor neurologic deficits, low CSF protein (< 50 mg/dL) and minimal or well controlled systemic disease, treatment-responsive histologies with remaining treatment options are prognostically favorable. Abbreviations: RT-radiation therapy, WBRT-whole brain radiation therapy, IT-intrathecal.

6.2. Chemotherapy and targeted therapy

focused course, even from the initial LM diagnosis. Symptomatic treatment involves management of numerous symptoms related to elevated ICP and infiltration of various parts of the neuroaxis (Table 1) [2,41]. Symptom management involves use of radiation, bevacizumab, placement of a ventriculoperitoneal shunt as well as specific symptom directed therapies listed in Table 1.

Blood-CSF barrier is formed by the choroid plexus and the arachnoid. This barrier is formed by tight junctions between apposing surfaces of choroid plexus epithelial cells that cover the choroid plexuses. The barrier is profoundly different from the BBB, and is much more permeable, as seen by the 300-fold difference in greater electrical resistance across the parenchymal endothelium (8000 Ω cm2) than the choroid plexus (26 Ω cm2) [49]. This allows some agents with poor brain parenchymal penetration to have better CSF concentration. In turn, knowledge of pharmacokinetics in the brain may not be directly applicable to the CSF and vice versa. It has been demonstrated that tumor cells facilitate the opening of the blood-CSF barrier, allowing the influx of potential mitogens into the CSF in turn propagating the tumor cell growth, survival, and proliferation in the CSF [50].

6.1. Radiation therapy While radiation has not definitely demonstrated improved survival, it is the mainstay for rapid symptom palliation and treatment of bulky disease [42]. It also may improve penetration of subsequent systemic treatments by mechanical disruption of the blood-brain barrier (BBB) and blood-CSF barrier [43,44]. A variety of radiation regimens have been employed to treat LM including focal radiation, whole brain radiation therapy (WBRT) and rarely cranio-spinal irradiation (CSI) [42]. Focal radiation (e.g. 10 × 3 Gy) can be used for bulky lesions, to alleviate CSF flow blockages, and palliate symptoms [42,45,46]. Aiming at covering the entire CSF compartment, craniospinal irradiation is occasionally considered. However, toxicity may be of concern in particular myelosuppression in patients who have received prior chemotherapy, as well as limitation to the use of subsequent chemotherapy. Proton beam irradiation may be circumvent some of these toxicities, and is currently under investigation in a trial for LM (NCT 03520504). Simultaneous or close sequential co-administration of radiation and systemic or IT chemotherapy may augment radiation-associated side effects. Particular caution should be taken when methotrexate is utilized in conjunction with WBRT, in light of the known severe leukoencephalopathy seen in older patients treated with such a regimen for primary CNS lymphoma [47]. A strategy for potentially minimizing cognitive toxicity would be WBRT with hippocampal avoidance and addition of memantine [48]. This strategy has proven beneficial within the context of brain metastases, but it is uncertain if this would hold true for LM.

6.3. Intrathecal therapy IT therapy is a means of delivering a chemotherapeutic agent directly to the therapeutic location (CSF) which helps circumvent the BCSFB. However, intrathecally administered agents will only disseminate within the tissue for a few millimeters of cells adjacent to the CSF, hence it is preferred in patients with non-bulky disease or postradiation in bulky disease who have limited options of CSF directed systemic treatment [51–53]. IT treatment can be administered via lumbar puncture or an intraventricular route. Intraventricular is often preferred as it allows for an easy procedure for drug administration and helps achieve uniform distribution in the CSF [54]. Superior survival has been demonstrated with this route of delivery [55].The most frequently utilized intraventricular access is an Ommaya reservoir. Various agents used via the intrathecal route are enlisted in Table 2. The addition of IT therapy to systemic treatment and radiation does not lead to survival benefit and is associated with an increased risk of neurotoxicity [56]. Potential complications include infection (meningitis), encephalopathy, seizure, myelopathy, aseptic or chemical meningitis, arachnoiditis, and delayed leukoencephalopathy [56,57]. Preservative5

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Table 2 Intrathecal agents. Agent

Mechanism

Regimen

CSF-half life

Methotrexate [119]

Cell cycle specific folate-antimetabolite

4.5–8 h

Cytarabine [120]

Cell-cycle specific Pyrimidine nucleoside analogue

a

Alkylating ethyleneimine compound

10–15 mg twice weekly for 4 wk., then 10–15 mg once weekly for 4 wk., then 10–15 mg once monthly 25–100 mg twice weekly for 4 wk., 25–100 mg once wkly for 4 wk., then 25–100 mg once monthly 10 mg twice weekly for 4 wk., then 10 mg once weekly for 4 wk., then 10 mg once a month 0.4 mg twice weekly X6 weeks followed by weekly for 6 weeks then twice monthly X4 months then monthly 0.5 mg once daily for 5 days repeat course Q3 weeks

Thiotepa [121]

*Topotecan [122,123]

Camptothecin analog

a

Etoposide [124] [125]

a

Trastuzumab [126] Rituximab [126] [127]

Cytotoxic effect through inhibition of DNA topoisomerase II Monoclonal antibody against Her2 Monoclonal antibody against CD20 antigen

a

12.5 to 25 mg increase to 100 mg weekly 10-25 mg. Once a week for week 1 then twice a week for 4 weeks

6h 3–4 min 2.6 h 9.6 h

10 mg dose: 22 h 25 mg dose: 35 h

Intrathecal chemotherapy agents are prepared on the day of use Methotrexate diluted to a concentration of 10 mg/ml using a ratio of 1 ml 25 mg/ml preservative free Methotrexate to 1.5 ml of preservative free 0.9% NaCl. Cytarabine diluted to a concentration of 50 mg/ml by diluting a 100 mg preservative free Cytarabine vial with 2 ml of preservative free 0.9% NaCl. a Not FDA Approved for intrathecal use.

involving brain parenchyma and CSF. Systemically administered HDMTX achieves CSF concentrations at least comparable to those achieved with IT therapy [63] and allows for a much intra-CNS tissue distribution. Bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), is utilized at times in LM. It is an agent which has demonstrated efficacy in some histologies such as non-small cell lung cancer when utilized as part of a combination regimen and is used routinely in primary CNS tumors such as glioblastoma. It is thought to decrease angiogenesis and decrease peritumoral edema. This first mechanism may diminish the potential for tumor growth upon landing on the surface of the brain parenchyma or dura. The second mechanism may help alleviate symptoms if substantial edema is present. Data regarding its use is limited primarily to case reports [64] [65,66].

free medications should be utilized for IT administration to avoid risk of preservative induced anaphylaxis and neurotoxicity. Erroneous administration of higher dose of IT therapy or incorrect IT therapy can be fatal. Accidental overdose can prevented by institutional policies of double checking medication details before IT administration and can be managed by CSF exchange and dexamethasone [58,59]. 6.4. Systemic therapy Agents which have activity on a specific histology outside the CNS can be considered for treatment of disease within the CNS. Most systemically administered chemotherapy regimens fail to penetrate into the CSF in sufficient concentrations, unless very high doses are systemically administered. This is due to the presence of the BCSFB which is located at the choroidal epithelium as well as the arachnoid membrane [60]. The barrier forming cells that separate the blood from the CSF compartment are joined by a continuous belt of tight junction proteins that seal the paracellular cleft and possess efflux transport proteins that prevent the entry of toxic compounds into the CSF and affect CSF drug concentration [60]. Small, lipid soluble molecules cross the barriers by transmembrane diffusion [61]. The charge of drug influences agents crossing the BCSFB as the CSF is normally more acidic than plasma [62]. A variety of means are utilized to achieve potentially effective concentrations in the CSF for the treatment of LM. As the volume of studies of systemic treatments for LM is limited, studies in brain metastases are often used as a rough proxy to suggest efficacy. Both clinicians and investigators need to understand, however, the limitations of applying knowledge from one disease location to another. CNS penetrating systemic treatment is preferred in particular in the setting of simultaneous progression of systemic disease as both CNS and extraCNS disease can be treated simultaneously.

6.6. Molecularly targeted treatments in patients with LM Various targeted therapies are available HER2 overexpressing breast cancers, NSCLC with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) positivity as well as melanoma with BRAF (V600E or V600K) mutation. For patients with HER2 positive breast cancer monoclonal antibodies like trastuzumab or pertuzumab will not penetrate sufficiently unless given at high doses in frequent intervals, many but not all small molecule tyrosine kinase inhibitors (TKI) may penetrate adequately. Lapatinib monotherapy in heavily pre-treated patients resulted in 2.6 to 6% response rates in the brain [67]. Lapatinib in combination with capecitabine showed even better CNS response rates of 20 to 38% in patients with Her2 positive breast cancer [68–70]. Lapatinib has been used as a potential radiosensitizer in combination with WBRT with good overall response rate but this combination is limited by toxicity in a phase 1 single arm study [71]. Other TKIs targeting HER2 including neratinib and tucatinib alone and in combination with capecitabine have shown activity in brain metastases but activity for LM has not been separately evaluated [72–74]. For patients with epidermal growth factor (EGFR) mutated nonsmall cell lung cancer (NSCLC) various TKIs have good BBB penetration. Gefitinib and erlotinib are first generation TKIs which penetrate CSF and erlotinib achieves higher CSF concentration [75]. In a retrospective study, improved survival was seen in patients with LM from NSCLC treated with TKIs for EGFR mutations who received intra-CSF chemotherapy (MTX or cytarabine) [35]. Standard dose erlotinib (150 mg daily) achieves CSF levels as low as 1% of plasma levels [76]. Weekly high dose of erlotinib up to 2000 mg is better tolerated and CSF concentration of 130 nM is achieved with a weekly dose of 1500 mg

6.5. Systemic chemotherapy and targeted agents Various systemic agents achieve adequate CSF concentrations and have been shown to have activity (albeit limited) in LM. Generally, this activity is histology and tumor subtype specific. We will highlight a few key classes of systemic therapies for LM and agents administered via systemic route are enlisted in Table 3. Methotrexate (MTX) has long been known to exhibit activity in systemic breast cancer. To overcome limitations of the BBB and BCSFB rapid systemic administration of high-doses of MTX (3.5–7 g/m2) are recommended. This therapeutic approach has demonstrated marked success in other CNS malignancies such as primary CNS lymphoma 6

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Table 3 Systemic agents for Leptomeningeal metastases. Agent

Dose

Mechanism

Use

HD-MTX [63] Temozolomide [128,129]

Up to 8 g/m2 75 mg/m2 with RT

Antifolate metabolite Alkylating

Gefitinib [75] Erlotinib [77,78] Afatinib [85] Osimertinib [87] Ceretinib [88] Alectinib [89] Brigatinib [93] Dabrafeninb [101] Vemurafinib [96–100] Trametinib [97]

250mh QD 1000-2000 mg weekly 40 mg QD 160 mg QD 750 mg QD 300-900 mg BID 90-240 mg 150 mg BID 960 mg BID 2 mg QD

1st generation EGFR TKI 1st generation EGFR TKI 2nd generation EGFR TKI 3rd generation EGFR-TKI ALK TKI ALK TKI ALK TKI BRAF inhibitor BRAF inhibitor MEK inhibitor

Breast Breast Lung NSCLC-EGFR mutated NSCLC-EGFR mutated NSCLC-EGFR mutated NSCLC-EGFR mutated ALK positive NSCLC ALK positive NSCLC ALK positive NSCLC Melanoma Melanoma Melanoma

Abbreviations: HD-MTX-high dose methotrexate, RT-radiation therapy, EGFR-epidermal growth factor receptor, TKI-tyrosine kinase inhibitor, NSCLC-non-small cell lung cancer, ALK- anaplastic lymphoma kinase.

treatment. Immune therapies both anti-PD1 and anti-CTLA4 have shown safety and activity in brain metastases and are now also being evaluated in LM. A phase 2 LM study with more than 80% breast cancer patients treated with the anti-PD-1 antibody pembrolizumab demonstrated that it is well tolerated in this patient population 44% of patients survived 3 months post enrollment [103]. Maturation of the data will be required to understand if there were any durable responses associated with prolonged survival as seen with checkpoint inhibitors when utilized in other clinical scenarios. Other immune therapies including nivolumab (PD1 Ab), ipilimumab (anti-CTLA4) and atezolimumab (anti–PD-L1) have shown activity in brain metastases but patients with LM have been excluded from these studies [104–110]. Ipilimumab has shown activity in patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic [105]. In a retrospective series of melanoma patients with LM, improved survival was seen with BRAF and PD-1 antibodies [111]. Efficacy in brain metastases raises hope that these findings may also translate to LM. Combining these therapies with RT might further augment their efficacy [106].

[77,78]. Second and third generation TKIs delay onset of CNS disease and are at times used first line for brain metastases from NSCLC with EGFR mutation [79–81]. Afatininb is a second generation TKI with poor CSF penetration rate of 2–3%. At a dose of 40-50 mg and is effective in treating LM from NSCLC with EGFR mutation [82,83]. In a phase I study afatinib 40 mg daily was reported to cause regression of brain metastasis [84]. A synergistic effect has been reported with combination of afatinib 40 mg daily along with cetuximab 250 mg/m2biweekly in a case with LM from NSCLC with improvement in LM lesions [85]. Osimertinib is a third generation TKI which demonstrated encouraging results in the phase I BLOOM study in patients with LM at a dose of 160 mg/day [86] [87]. For ALK translocated NSCLC, ALK inhibitors have been shown to have activity in parenchymal brain metastases [88]. Compared to the older generation ALK inhibitors such as crizotinib with low CSF penetration rate (0.26%), newer agents alectinib and ceretinib have higher CSF penetration rates (86% and 15% respectively) [89,90]. Newer ALK inhibitors like ceretinib and alectinib have been reported to have activity in LM [88,91,92]. Next generation ALK inhibitor brigatinib (90240 mg) has shown promising results in phase I/II study of patients with brain metastases including LM patients [93]. Targeted treatments for melanoma include BRAF and MEK inhibitors as well as immune therapy with checkpoint inhibition. Vemurafinib and dabrafenib have restricted CNS penetration but dabrafenib has higher penetration as compared to vemurafenib [94,95]. Both have shown meaningful CNS responses in melanoma patients with brain metastases as well as in some cases of LM [96–101]. Combination of dabrafenib and trametinib has shown clinical benefit in melanoma with brain metastasis but patients with LM were excluded in this study [102]. Trametinib is a MEK inhibitor used with dabrafenib for unresectable or metastatic melanoma with BRAF (V600E or V600K) mutations to overcome resistance encountered downstream to BRAF in the MAPK signaling pathway.

7. Future directions Various diagnostic and therapeutic efforts are ongoing for early detection, tools to measure treatment response and novel treatments to improve survival as well as quality of life for patients with LM. Cell-free tumor DNA (ctDNA) in the CSF is being investigated as a complementary tool for the diagnosis and characterization of LM and facilitate detection of actionable genomic alterations and monitor responses to therapy in patients with LM [112]. CSF ctDNA can reveal somatic mutations in 100% of metastatic brain tumor patients with positive cytology and in 25% of patients with negative cytology [112,113]. It has been reported to be more sensitive than cytology in detecting LM in an autopsy study of breast cancer patients [112]. Novel treatments including proton radiation to the entire craniospinal axis to circumvent toxicities associated with CSI (NCT03520504), immunotherapy as well as chemotherapy with better BCSFB penetration hold promise for future improvement in prognosis. Chemotherapy with paclitaxel trevatide (ANG1005), for HER2-negative breast with newly diagnosed LM (NCT03613181) is under investigation [114]. Paclitaxel trevatide is a novel taxane derivative, consisting of 3 paclitaxel molecules covalently linked to angiopep-2, designed to cross the BCSFB [114]. Ongoing check point inhibitor trials include pembrolizumab (NCT02939300) and combination of nivolumab and ipilimumab (NCT03091478) for LM with solid tumors. Additional immune therapies being investigated include chimeric antigen receptor (CAR)-engineered T cell therapy where patients T cells are genetically engineered to specifically recognize a tumor antigen by

6.7. Immune therapies Immune effectors recognize and destroy tumor cells and provide long-term immune surveillance. A variety of immunotherapies, including cellular therapies, have been incorporated into cancer treatment. Treatment with immune check point blockade (ICB) anti- programmed death1 (PD1), anti-programmed death ligand 1 (PD-L1) or anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) block inhibitory signals for T cells and allows the adaptive immune system to target tumor cells. In melanoma and NSCLC immune checkpoint inhibitors have shown safety and CNS responses as monotherapy as well as combination 7

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adoptive transfer CAR-engineered T cells [115]. EGFR may be a potential tumor antigen for CAR natural killer (NK) cells to target for the treatment of brain metastases from breast and lung cancer (NCT03330834) [116]. Intraventricular delivery of HER2-specific CAR T-cell for the treatment of LM from breast cancer is being investigated [117]. Other investigational immune treatments include personalized vaccine therapies (NCT02808416) as well as interleukin based therapies [118]. Novel approaches for drug delivery using ultrasound technologies to increase permeability of the BBB and BCSF are under investigation.

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