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Leptomeningeal metastases from solid tumours

Leptomeningeal metastases from solid tumours short review memo (2021) 14:192–197 https://doi.org/10.1007/s12254-021-00693-6 Silvia Hofer · Emilie Le Rhun Received: 21 January 2021 / Accepted: 17 February 2021 / Published online: 16 March 2021 © The Author(s) 2021 Summary Leptomeningeal metastases from solid tu- (3) melanoma. The highest incidence of LM appears mours are increasingly being diagnosed and require a to be in melanoma (23%) and lung cancer (9–25%) careful assessment by an interdisciplinary neuro-on- then followed by breast cancer (5%). Considering cological tumour board for adequate diagnosis, ther- the high incidence of breast cancer worldwide, in apy planning and optimal care of the affected patients. absolute numbers it constitutes the most common aetiology of LM. Rarely, leptomeningeal metastases Keywords Carcinomatous meningitis · are a first tumour manifestation. Concurrent systemic Leptomeningeal carcinomatosis · Leptomeningeal disease progression is seen in up to 60–70% of pa- metastases · Neoplastic meningitis · Intrathecal tients. Brain metastases are noted in about 40%, half therapy of them progressing at leptomeningeal metastases diagnosis, new brain metastases have been reported An increasing number of patients with metastatic can- in 20% [2, 3]. cer are developing leptomeningeal dissemination due to Prognosis of leptomeningeal tumour manifestation better therapies and longer survival. In a brief review, we is generally poor, with a median survival limited to will focus on leptomeningeal disease arising from solid tu- a few months in most patient cohorts, with the ex- mours and inform about current management and future ception of molecularly altered tumours which are ac- directions. cessible to targeted drugs and a longer disease control may therefore be expected. Leptomeningeal metastases (LM) are defined by A literature search on this particular tumour man- the presence of metastatic tumour cells within the ifestation provides information on the following leptomeninges and the subarachnoid space. Overall, terms: “meningeosis carcinomatosa”, “carcinomatous leptomeningeal involvement is diagnosed in about meningitis”, “neoplastic meningitis”, “leptomeningeal 10–15% of patients with metastatic solid tumours, carcinomatosis” and “leptomeningeal metastases”. with an increasing tendency, due to longer survival Hereafter, the term leptomeningeal metastases will of patients with the associated tumours and better be used, abbreviated as “LM”. access to modern imaging. Three tumour entities are particularly prone to spread to the meninges: Pathophysiology (1) breast cancer [1], (2) lung cancer, notably molec- ular driven subtypes of NSCLC and SCLC, and, The leptomeninges and the subarachnoid space are reached by the haematogenous route through the “blood–leptomeningeal barrier (BLB)”, a vascular S. Hofer () structure, which is semipermeable at least for tu- Department of Neurology, University Hospital Zurich, mour and immune cells. Cancer cells that reach the Zurich, Switzerland silvia.hofer@usz.ch brain microvasculature may also cross the “blood–CSF barrier” via the choroid plexus to enter the ventricles E. Le Rhun and the leptomeningeal space. Furthermore, direct Departments of Neurology and Neurosurgery, Clinical tumour cell invasion can occur from infiltrating brain Neuroscience Center and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland metastases. Finally, tumour cells can migrate via 192 Leptomeningeal metastases from solid tumours K short review vessels of the skull, from vertebral bodies and via perineural and perivascular routes. Rather rarely, leptomeninges are colonized iatrogenically, i.e. after brain metastasis resection [4]. Various CNS barriers hinder—at least partially—therapeutic drug concen- trations in the brain after systemic administration [5]. Diagnostics Symptoms may initially be discrete, unspecific and variable, and may involve multiple localizations i.e. any part of the neuraxis. Typical symptoms include headache, nausea and vomiting, mental changes, dizziness and drowsiness, gait difficulties, cranial nerve palsies with diplopia, visual disturbances, hear- ing loss, sensorimotor deficits of the extremities, cauda equine syndrome, and radicular neck and back pain. Contrast-enhanced magnetic resonance imag- Fig. 1 Nodular (a) and linear (b) leptomeningeal tumour ing (MRI) is the first mandatory diagnostic procedure. growth The whole cerebrospinal neuraxis should always be assessed to determine the extent of the disease. MRI findings include sulcal and foliar enhancements, lin- CSF cytology. In case of extensive nodular and symp- ear ependymal and cranial nerve root enhancement tomatic manifestation, local radiotherapy (RT) is rec- but also leptomeningeal enhancing nodules. Of note, ommended, whereas 1–2 mm layers or freely circu- about 20–30% of patients with LM have a normal lating tumour cells are probably more accessible to or false-negative MRI. After exclusion of a hydro- intrathecal (i.th.) and systemic therapy. We would cephalus, diagnosis of LM is confirmed by malignant rather not recommend i.th. therapy for nodular dis- cells in the CSF. It should be noted that the first ease without a positive CSF cytology on repeated sam- cerebrospinal fluid sample obtained is only diagnos- pling through lumbar puncture. RT may also be an tic in about 50% and should be repeated if deemed option for the treatment of CSF flow blocks. necessary [3]. For quality reasons, it is important Without any treatment, leptomeningeal spread is to ensure a sufficient amount of cerebrospinal fluid fatal within a few weeks. With conventional systemic (5–10 ml) and rapid processing of the material (within therapy, median survival is about 3–6 months. Tar- one hour). Tumour markers, such as CEA or CA geted therapies can achieve much longer lasting tu- 125, when present in the primary tumour, can be mour control, especially in HER-2 positive, EGFRmut determined in the CSF for diagnostic and follow-up and ALK driven tumours. purposes. CSF tumour markers reflect intrathecal production; the concentration is higher than in the Local therapeutic options serum. They may also support the diagnosis in case of a lack of tumour cells in the CSF; however their role Surgical intervention for leptomeningeal disease is in clinical practice, is limited [6]. Circulating tumour rarely needed, except for the insertion of an intra- DNA (ctDNA) in the CSF is a complementary tool ventricular reservoir for drug administration or for for diagnosis and characterization of LM. ctDNA may a ventriculoperitoneal shunt in case of intracranial detect actionable genomic alterations and resistance hypertension. Hereby, blockage of the shunt due mutations not present in metastases in the periphery. to tumour cell clusters is a dreaded complication. In the absence of tumour cells in the CSF, neurolog- The overall complication rate of ventriculoperitoneal ical symptoms and typical craniospinal MR findings shunts is estimated to be between 9 and 15% [7]. strongly support the diagnosis of cancer in a patient. Hydrocephalus can also be corrected by third ven- triculostomy, using no implants and having little risk of blockage. The decision on how to manage LM-as- Leptomeningeal growth pattern and therapeutic sociated hydrocephalus is complex and requires close consequences collaboration amongst physicians, patients, and/or A distinction is made between nodular tumour growth, proxies with a focus on patient’s quality-of-life [8]. adherent to the meninges, linear spread and freely Focal radiotherapy is indicated in symptomatic floating tumour cells or a combination of these man- nodular lesions, to correct cerebrospinal fluid circu- ifestations (Fig. 1). lation, for rapid treatment of tumoural cranial nerve Therapeutic consequences result from these dif- affections, cauda equina symptoms or for the simul- ferent growth patterns, as assessed by imaging and taneous treatment of brain metastases. Whole brain K Leptomeningeal metastases from solid tumours 193 short review radiotherapy (WBRT) covers a large part of the cere- fluid”, “brain parenchyma” and “blood” is most in- brospinal fluid space and may be indicated in the teresting, partly unexpected and not yet fully un- absence of other options. However, WBRT does not derstood. Intrathecally administered antibodies may confer a survival advantage, and comes along with work partly through antibody-dependent cellular tox- serious neurocognitive disorders. Irradiation of the icity (ADCC) or complement-dependent cytotoxicity whole cerebrospinal axis is not recommended due to (CDC) [12]. its toxicity. For intraventricularly administered rituximab, a phar- macokinetic model was developed that suggests a certain penetration of antibodies into the brain Intrathecal therapies parenchyma. Furthermore, elimination of the an- Intrathecal (i.th.) administration of suitable drugs is tibodies from the CSF into the serum has been recommended under the condition of floating tumour demonstrated by pharmacokinetic studies. High, cells (CSF cytology) and/or linear tumour spread (up i.e. therapeutic, serum levels have been measured to 1–2 mm thickness) [3]. Advantageous for successful after intrathecal trastuzumab and rituximab with- intrathecal treatment is, as for any therapeutic inter- out systemic treatment [12–14]. A pooled analysis of vention, good tumour control outside of the CNS and 58 patients with HER-2 positive breast cancer con- an adequate performance status without severe neu- firmed safety and efficacy of i.th. trastuzumab [15]. rological deficits. A more favourable drug distribution A first phase I dose escalation study with 16 patients can be achieved by a reservoir with direct access to recommends 150 mg i.th. trastuzumab weekly [16]. the ventricles (e.g. Ommaya reservoir) compared to Our own observations with CSF and serum trough repetitive lumbar punctures. The revision rate of such levels could show that even 150 mg every 3 weeks is a reservoir in trained hands is 7–8%, while the in- effective to control leptomeningeal disease, in one fection rate is reported to be 5–10% [9]. In case of patient lasting for more than 4 years [17]. Time from suspected obstruction, CSF flow studies may be per- the first i.th. trastuzumab until improvement of neu- formed to evaluate the patency of the CSF circulation rological symptoms, and lack of detectable tumour before moving to intrathecal therapy. cells in the CSF was 3, 2, and 1 month, respectively, There are no randomized studies (RCT) to compare in 3 subsequent patients. Disappearance of MR con- intrathecal therapy versus “best supportive care” for trast-uptake was observed after 4 and 3 months, solid tumours. However, there are randomized data respectively. All 3 patients had previously received on systemic therapy with and without additional in- WBRT. Trastuzumab CSF concentrations (trough trathecal therapy in breast cancer. A recent study level) > 0.1 mg/L allowed leptomeningeal tumour with i.th. liposomal cytarabine (drug currently not control over time in our small series. Remarkably, available) showed prolonged progression-free survival trastuzumab serum concentrations after 3-weekly (PFS) for leptomeningeal involvement and a trend to- intrathecal application alone reached 30 mg/L, cor- wards an improved survival [10]. An older RCT, with responding to therapeutic serum levels [13]. The some methodological weaknesses, did not report such elimination process of trastuzumab and other an- an advantage for the combination of systemic and in- tibodies from the CSF into the blood and the best trathecal chemotherapy. Furthermore, increased neu- combination with systemic treatment remains to be rotoxicity with i.th MTX was observed and an unex- investigated. Moreover, the question regarding dura- pected high complication rate with the ventricular de- tion of i.th. antibodies beyond clinical improvement vices occurred in this study [11]. is still unresolved. Of note, the old drugs, which we have been us- No acute neurotoxicity has been described for ing intrathecally for more than 40 years, are not well i.th. monoclonal antibodies such as rituximab, suited to achieve good tumour control in most of the trastuzumab, bevacizumab, nivolumab or panitu- affected cancers. MTX, thiotepa, cytarabine, gemc- mumab; however, long-term toxicity over several itabine, topotecan and etoposide are not the preferred years cannot be excluded. Provided that intrathe- drugs for most common tumours that metastasize to cally administered immune checkpoint inhibitors the leptomeninges and all of them have a short half- may show efficacy in the near future in controlling life (4–8 h), which is why these drugs have to be ad- leptomeningeal disease of immune-responsive tu- ministered two times per week, at least initially. Other mours such as melanoma, NSCLC, SCLC, renal cell disadvantages are local and sometimes irreversible and triple-negative breast cancer, the drug reservoir toxicities (e.g. arachnoiditis, myelopathy, progressive “CSF” could become an interesting therapeutic niche. leukoencephalopathy). Further pharmacokinetic studies will have to show In recent years, some monoclonal antibodies have whether intrathecal antibody therapy alone may sub- been successfully administered intrathecally and pre- stitute for systemic administration. liminary experience has been gathered in phase I studies, small case series and individual observations. Activity of intrathecally administered monoclonal an- tibodies in the three compartments “cerebrospinal 194 Leptomeningeal metastases from solid tumours K short review in patients with treated, asymptomatic brain metas- Systemic therapies tases [20]. Few specific data are available for leptomeningeal dis- A post hoc exploratory subgroup analysis of the ease and systemic therapy; most have been extrapo- KAMILLA trial in 398 anti-HER-2 pretreated patients lated from patients with brain metastases or advanced with asymptomatic BM represents the largest cohort disease. treated with T-DM1. A clinical significant benefit was Classical chemotherapy has been used for lep- observed in patients with and without prior radiother- tomeningeal disease and some have proven to be apy [21]. Combination strategies with immunother- active in sensitive tumours, among others, 5-fluo- apy are worth exploring, as T-DM1 treatment seems rouracil, capecitabine, pemetrexed cisplatin, carbo- effective in increasing the presence of TILs [22]. platin, vinorelbine, gemcitabine, high-dose methotrex- A non-randomized phase II study with the CNS- ate (≥3g/m ), thiotepa, high-dose cytarabine, etopo- penetrant CDK4 inhibitor abemaciclib for hormone side, eribulin. receptor-positive breast cancer patients with brain The anti-HER-2 monoclonal antibodies trastuzumab and leptomeningeal metastases did not meet its pri- and pertuzumab have in general modest activity mary endpoint (intracranial response rate, iORR), when administered as monotherapy in metastatic but an intracranial clinical benefit rate (iCBR) was de- HER-2-positive disease and they do not cross an in- scribed for the cohort with highly pretreated hormone tact blood–brain barrier. Concomitant chemotherapy receptor-positive, HER-2-negative breast cancer pa- administration is needed for optimal extracranial ac- tients. iCBR in the study was defined as CR, PR or SD tivity. In addition, there is statistically and clinically ≥ 6 months. Fourteen out of 55 patients of cohort A significant improved response and time to progres- (hormone-receptor-positive, HER-2-negative) had an sion for the continuation of trastuzumab beyond iPR or iSD > 6 months, resulting in an iCBR of 24.1%. progression in the management of women with HER- [23]. 2-positive advanced breast cancer [18] and it has been Activity of anti-hormonal drugs, such as tamox- suggested that an improvement of systemic disease ifen or aromatase inhibitors, has been reported in the control delays the onset of brain metastasis (BM), as brain and in the leptomeninges and could potentially has been demonstrated in the CLEOPATRA trial [19]. be considered in responsive tumours [24]. Similar observations are reported for the anti- Next generation targeted tyrosine kinase inhibitors HER-2 antibody-drug conjugate ado-trastuzumab (TKI) with small molecular weight (400–500 D), low or emtansine (T-DM1) where the chemotherapy back- lacking dependence on efflux transporters (e.g. P-gly- bone has been directly linked to the antibody, allowing coprotein, Pgp)—not a sole criterion though—have targeted tumour delivery of an otherwise toxic com- been reported to have clinically meaningful activity pound, DM1, a potent microtubule polymerization in the CNS and may even have preventive potential inhibitor. on the formation of new LM or brain metastases in T-DM1 activity in central nervous system metasta- tumours with corresponding actionable targets. sis was assessed in a retrospective, exploratory analy- Examples are osimertinib for EGFRmut, alectinib sis of the EMILIA randomized phase III trial, compar- for ALK- and RET-, lorlatinib for ALK—and ROS 1 and ing safety and efficacy of T-DM1 with standard of care, brigatinib for EGFR-, ALK- and ROS1-altered NSCLC, capecitabine and lapatinib. In participants who had but also vemurafenib or dabrafenib with and with- been previously treated with trastuzumab and a tax- out MEK-inhibitors for BRAFV600Emut tumours (Ta- ane, the analysis suggested that T-DM1 may confer ble 1). They have all shown to result in impressive a survival advantage over capecitabine and lapatinib and often durable intracranial responses [25]. Exem- Table 1 Selected molecular targeted agents for LM from NSCLC (adapted from [25]) Drug Target MW Substrate for efflux transport CNS penetration (CSF/plasma or CSF/blood) Erlotinib EGFR 393 Yes 2.8% to 3.3% Gefitinib EGFR 447 Yes 1.13% Afatinib EGFR 486 Yes 1.65% Osimertinib EGFR (T790M) 500 Yes 2.5% to 16% Zorifertinib EGFR 460 No 100% Crizotinib ALK, MET, ROS1 450 Yes 0.26% Ceritinib ALK, ROS1 558 Yes 15% Alectinib ALK, RET 483 No 63% to 94% Brigatinib ALK, ROS1, EGFR 529 Yes no data Lorlatinib ALK, ROS1 406 Yes, but low 31% to 96% Vemurafenib BRAF 490 Yes 0.98% LM leptomeningeal metastases, NSCLC non-small cell lung cancer, MW molecular weight K Leptomeningeal metastases from solid tumours 195 short review plary, in ALK-TKI refractory NSCLC patients with LM, is a heterogeneous uptake into the leptomeninges, the intracranial ORR, intracranial disease control rate, which may explain, at least in part, their limited effi- median duration of treatment and median PFS were cacy. Some patients may benefit from systemic treat- 45% and 91%, 5.3 months, and 9.3 months respec- ment beyond progression in the CNS if they are of- tively [26]. A higher incidence of LM was observed in fered local treatment for their intracranial disease. For NSCLC patients harbouring EGFR mutations after an all these considerations, the neurological and general effective EGFR TKI treatment. In particular, mutation condition and the patient’s wish must be taken into L858R potentially predicts a higher risk of LM com- account in a difficult-to-treat disease manifestation pared with deletion of exon 19. These results highlight with still poor outcome. the importance of determining the current mutational status, preferentially from liquid biopsies of the CSF Future directions [25, 27]. Lapatinib is effective to a lesser extent for HER- The CSF space is a challenging niche for metastatic 2-positive tumours due to its dependence on the tumour cells. Recent research focused on the bio- Pgp. Tucatinib, a highly selective TKI against HER-2, chemical composition of the CSF in the setting of has reported activity in 75 untreated patients with leptomeningeal metastases. Mechanisms of cell sur- HER-2-positive brain metastases in combination with vival and distinct gene expression signatures were dis- trastuzumab and capecitabine; intracranial ORR of covered. Some appear to act via a high-affinity iron 47.3% could be reached in the HER2CLIMB trial [28]. transport system to maintain iron-dependent cellu- While the current evidence on the activity of TKIs lar survival functions and the suppression of local comes from case series and retrospective studies with macrophage activation by iron deprivation. Whether LM, prospectively collected data are becoming avail- this iron-capturing system also confers increased sur- able in rapid succession. vival of circulating tumour cells requires further in- Immune checkpoint inhibitors (IO) have been vestigations [32]. shown to be effective in the brain by exerting activity Cell-free circulating tumour DNA (ctDNA) in the on BM and LM indirectly by T cell responses [29, 30] CSF holds useful information regarding diagnosis to and thus might even have prophylactic potential, as better characterize LM, detect actionable genomic al- has been suggested by a lower incidence of new BM terations and monitor responses to therapy [33]. with durvalumab in NSCLC [31]. Combining IO with RT might further augment the efficacy (Table 2). Take Home Message Leptomeningeal metastases should be treated ac- Concluding remarks cording to the clinical, MRI and cytological presen- For leptomeningeal disease intrathecal therapy seems tation, taking into consideration the general and particularly useful when targeted drugs with a long neurological status, molecular characteristics, other half-life are available, e.g. trastuzumab. Systemic metastatic sites and prior treatments. therapies with the ability to overcome brain barriers  Promising approaches are under development and are only effective if tumour cells are sensitive. A com- trials should be conducted specifically for this patient mon feature of all systemically administered drugs population. Funding OpenAccessfundingprovidedbyUniversitätZürich. Table 2 Drugs most commonly used for leptomeningeal Conflict of interest E. Le Rhun has received honoraria for disease from solid tumours lectures or advisory board participation or consulting from Intrathecal drugs Abbvie, Adastra, Daiichi Sankyo, Tocagen, Leo Pharma and Methotrexate, Initially 2 ×/week Seattle Genetics. S. Hofer declares that she has no competing 10–15 mg interests. Thiotepa, 10 mg Initially 2 ×/week Open Access This article is licensed under a Creative Com- Trastuzumab, 150 mg Weekly to three weekly mons Attribution 4.0 International License, which permits Systemic drugs use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit Next generation TKI According to target, taking into account resistance to the original author(s) and the source, provide a link to mechanisms the Creative Commons licence, and indicate if changes were Chemotherapeutic According to sensitivity or resistance of the tumour made. The images or other third party material in this article drugs are included in the article’s Creative Commons licence, unless HER-2 directed thera- T-DM1 and next generation TKIs indicated otherwise in a credit line to the material. If material pies is not included in the article’s Creative Commons licence and Anti-hormone thera- Tamoxifen, aromatase inhibitors your intended use is not permitted by statutory regulation or pies exceeds the permitted use, you will need to obtain permis- CDK 4 inhibitors Abemaciclib sion directly from the copyright holder. To view a copy of this Immunotherapies PD-L1 antibodies licence, visit http://creativecommons.org/licenses/by/4.0/. 196 Leptomeningeal metastases from solid tumours K short review cer treated with pertuzumab, trastuzumab, and docetaxel: References results from the randomized phase III study CLEOPATRA. AnnOncol. 2014;25:1116–21. 1. Abouharb S, et al. Leptomeningeal disease and breast 20. Krop IE, et al. 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Trastuzumab beyond progres- tional oncology congresses see: sion in human epidermal growth factor receptor 2-posi- http://www.springermedizin.at/ tive advanced breast cancer: a German breast group 26/ breast international group 03-05 study. J Clin Oncol. memo-inoncology 2009;27:1999–2006. 19. SwainSM,etal. Incidenceofcentralnervoussystemmetas- tases in patients with HER2-positive metastatic breast can- K Leptomeningeal metastases from solid tumours 197 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Leptomeningeal metastases from solid tumours

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short review memo (2021) 14:192–197 https://doi.org/10.1007/s12254-021-00693-6 Silvia Hofer · Emilie Le Rhun Received: 21 January 2021 / Accepted: 17 February 2021 / Published online: 16 March 2021 © The Author(s) 2021 Summary Leptomeningeal metastases from solid tu- (3) melanoma. The highest incidence of LM appears mours are increasingly being diagnosed and require a to be in melanoma (23%) and lung cancer (9–25%) careful assessment by an interdisciplinary neuro-on- then followed by breast cancer (5%). Considering cological tumour board for adequate diagnosis, ther- the high incidence of breast cancer worldwide, in apy planning and optimal care of the affected patients. absolute numbers it constitutes the most common aetiology of LM. Rarely, leptomeningeal metastases Keywords Carcinomatous meningitis · are a first tumour manifestation. Concurrent systemic Leptomeningeal carcinomatosis · Leptomeningeal disease progression is seen in up to 60–70% of pa- metastases · Neoplastic meningitis · Intrathecal tients. Brain metastases are noted in about 40%, half therapy of them progressing at leptomeningeal metastases diagnosis, new brain metastases have been reported An increasing number of patients with metastatic can- in 20% [2, 3]. cer are developing leptomeningeal dissemination due to Prognosis of leptomeningeal tumour manifestation better therapies and longer survival. In a brief review, we is generally poor, with a median survival limited to will focus on leptomeningeal disease arising from solid tu- a few months in most patient cohorts, with the ex- mours and inform about current management and future ception of molecularly altered tumours which are ac- directions. cessible to targeted drugs and a longer disease control may therefore be expected. Leptomeningeal metastases (LM) are defined by A literature search on this particular tumour man- the presence of metastatic tumour cells within the ifestation provides information on the following leptomeninges and the subarachnoid space. Overall, terms: “meningeosis carcinomatosa”, “carcinomatous leptomeningeal involvement is diagnosed in about meningitis”, “neoplastic meningitis”, “leptomeningeal 10–15% of patients with metastatic solid tumours, carcinomatosis” and “leptomeningeal metastases”. with an increasing tendency, due to longer survival Hereafter, the term leptomeningeal metastases will of patients with the associated tumours and better be used, abbreviated as “LM”. access to modern imaging. Three tumour entities are particularly prone to spread to the meninges: Pathophysiology (1) breast cancer [1], (2) lung cancer, notably molec- ular driven subtypes of NSCLC and SCLC, and, The leptomeninges and the subarachnoid space are reached by the haematogenous route through the “blood–leptomeningeal barrier (BLB)”, a vascular S. Hofer () structure, which is semipermeable at least for tu- Department of Neurology, University Hospital Zurich, mour and immune cells. Cancer cells that reach the Zurich, Switzerland silvia.hofer@usz.ch brain microvasculature may also cross the “blood–CSF barrier” via the choroid plexus to enter the ventricles E. Le Rhun and the leptomeningeal space. Furthermore, direct Departments of Neurology and Neurosurgery, Clinical tumour cell invasion can occur from infiltrating brain Neuroscience Center and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland metastases. Finally, tumour cells can migrate via 192 Leptomeningeal metastases from solid tumours K short review vessels of the skull, from vertebral bodies and via perineural and perivascular routes. Rather rarely, leptomeninges are colonized iatrogenically, i.e. after brain metastasis resection [4]. Various CNS barriers hinder—at least partially—therapeutic drug concen- trations in the brain after systemic administration [5]. Diagnostics Symptoms may initially be discrete, unspecific and variable, and may involve multiple localizations i.e. any part of the neuraxis. Typical symptoms include headache, nausea and vomiting, mental changes, dizziness and drowsiness, gait difficulties, cranial nerve palsies with diplopia, visual disturbances, hear- ing loss, sensorimotor deficits of the extremities, cauda equine syndrome, and radicular neck and back pain. Contrast-enhanced magnetic resonance imag- Fig. 1 Nodular (a) and linear (b) leptomeningeal tumour ing (MRI) is the first mandatory diagnostic procedure. growth The whole cerebrospinal neuraxis should always be assessed to determine the extent of the disease. MRI findings include sulcal and foliar enhancements, lin- CSF cytology. In case of extensive nodular and symp- ear ependymal and cranial nerve root enhancement tomatic manifestation, local radiotherapy (RT) is rec- but also leptomeningeal enhancing nodules. Of note, ommended, whereas 1–2 mm layers or freely circu- about 20–30% of patients with LM have a normal lating tumour cells are probably more accessible to or false-negative MRI. After exclusion of a hydro- intrathecal (i.th.) and systemic therapy. We would cephalus, diagnosis of LM is confirmed by malignant rather not recommend i.th. therapy for nodular dis- cells in the CSF. It should be noted that the first ease without a positive CSF cytology on repeated sam- cerebrospinal fluid sample obtained is only diagnos- pling through lumbar puncture. RT may also be an tic in about 50% and should be repeated if deemed option for the treatment of CSF flow blocks. necessary [3]. For quality reasons, it is important Without any treatment, leptomeningeal spread is to ensure a sufficient amount of cerebrospinal fluid fatal within a few weeks. With conventional systemic (5–10 ml) and rapid processing of the material (within therapy, median survival is about 3–6 months. Tar- one hour). Tumour markers, such as CEA or CA geted therapies can achieve much longer lasting tu- 125, when present in the primary tumour, can be mour control, especially in HER-2 positive, EGFRmut determined in the CSF for diagnostic and follow-up and ALK driven tumours. purposes. CSF tumour markers reflect intrathecal production; the concentration is higher than in the Local therapeutic options serum. They may also support the diagnosis in case of a lack of tumour cells in the CSF; however their role Surgical intervention for leptomeningeal disease is in clinical practice, is limited [6]. Circulating tumour rarely needed, except for the insertion of an intra- DNA (ctDNA) in the CSF is a complementary tool ventricular reservoir for drug administration or for for diagnosis and characterization of LM. ctDNA may a ventriculoperitoneal shunt in case of intracranial detect actionable genomic alterations and resistance hypertension. Hereby, blockage of the shunt due mutations not present in metastases in the periphery. to tumour cell clusters is a dreaded complication. In the absence of tumour cells in the CSF, neurolog- The overall complication rate of ventriculoperitoneal ical symptoms and typical craniospinal MR findings shunts is estimated to be between 9 and 15% [7]. strongly support the diagnosis of cancer in a patient. Hydrocephalus can also be corrected by third ven- triculostomy, using no implants and having little risk of blockage. The decision on how to manage LM-as- Leptomeningeal growth pattern and therapeutic sociated hydrocephalus is complex and requires close consequences collaboration amongst physicians, patients, and/or A distinction is made between nodular tumour growth, proxies with a focus on patient’s quality-of-life [8]. adherent to the meninges, linear spread and freely Focal radiotherapy is indicated in symptomatic floating tumour cells or a combination of these man- nodular lesions, to correct cerebrospinal fluid circu- ifestations (Fig. 1). lation, for rapid treatment of tumoural cranial nerve Therapeutic consequences result from these dif- affections, cauda equina symptoms or for the simul- ferent growth patterns, as assessed by imaging and taneous treatment of brain metastases. Whole brain K Leptomeningeal metastases from solid tumours 193 short review radiotherapy (WBRT) covers a large part of the cere- fluid”, “brain parenchyma” and “blood” is most in- brospinal fluid space and may be indicated in the teresting, partly unexpected and not yet fully un- absence of other options. However, WBRT does not derstood. Intrathecally administered antibodies may confer a survival advantage, and comes along with work partly through antibody-dependent cellular tox- serious neurocognitive disorders. Irradiation of the icity (ADCC) or complement-dependent cytotoxicity whole cerebrospinal axis is not recommended due to (CDC) [12]. its toxicity. For intraventricularly administered rituximab, a phar- macokinetic model was developed that suggests a certain penetration of antibodies into the brain Intrathecal therapies parenchyma. Furthermore, elimination of the an- Intrathecal (i.th.) administration of suitable drugs is tibodies from the CSF into the serum has been recommended under the condition of floating tumour demonstrated by pharmacokinetic studies. High, cells (CSF cytology) and/or linear tumour spread (up i.e. therapeutic, serum levels have been measured to 1–2 mm thickness) [3]. Advantageous for successful after intrathecal trastuzumab and rituximab with- intrathecal treatment is, as for any therapeutic inter- out systemic treatment [12–14]. A pooled analysis of vention, good tumour control outside of the CNS and 58 patients with HER-2 positive breast cancer con- an adequate performance status without severe neu- firmed safety and efficacy of i.th. trastuzumab [15]. rological deficits. A more favourable drug distribution A first phase I dose escalation study with 16 patients can be achieved by a reservoir with direct access to recommends 150 mg i.th. trastuzumab weekly [16]. the ventricles (e.g. Ommaya reservoir) compared to Our own observations with CSF and serum trough repetitive lumbar punctures. The revision rate of such levels could show that even 150 mg every 3 weeks is a reservoir in trained hands is 7–8%, while the in- effective to control leptomeningeal disease, in one fection rate is reported to be 5–10% [9]. In case of patient lasting for more than 4 years [17]. Time from suspected obstruction, CSF flow studies may be per- the first i.th. trastuzumab until improvement of neu- formed to evaluate the patency of the CSF circulation rological symptoms, and lack of detectable tumour before moving to intrathecal therapy. cells in the CSF was 3, 2, and 1 month, respectively, There are no randomized studies (RCT) to compare in 3 subsequent patients. Disappearance of MR con- intrathecal therapy versus “best supportive care” for trast-uptake was observed after 4 and 3 months, solid tumours. However, there are randomized data respectively. All 3 patients had previously received on systemic therapy with and without additional in- WBRT. Trastuzumab CSF concentrations (trough trathecal therapy in breast cancer. A recent study level) > 0.1 mg/L allowed leptomeningeal tumour with i.th. liposomal cytarabine (drug currently not control over time in our small series. Remarkably, available) showed prolonged progression-free survival trastuzumab serum concentrations after 3-weekly (PFS) for leptomeningeal involvement and a trend to- intrathecal application alone reached 30 mg/L, cor- wards an improved survival [10]. An older RCT, with responding to therapeutic serum levels [13]. The some methodological weaknesses, did not report such elimination process of trastuzumab and other an- an advantage for the combination of systemic and in- tibodies from the CSF into the blood and the best trathecal chemotherapy. Furthermore, increased neu- combination with systemic treatment remains to be rotoxicity with i.th MTX was observed and an unex- investigated. Moreover, the question regarding dura- pected high complication rate with the ventricular de- tion of i.th. antibodies beyond clinical improvement vices occurred in this study [11]. is still unresolved. Of note, the old drugs, which we have been us- No acute neurotoxicity has been described for ing intrathecally for more than 40 years, are not well i.th. monoclonal antibodies such as rituximab, suited to achieve good tumour control in most of the trastuzumab, bevacizumab, nivolumab or panitu- affected cancers. MTX, thiotepa, cytarabine, gemc- mumab; however, long-term toxicity over several itabine, topotecan and etoposide are not the preferred years cannot be excluded. Provided that intrathe- drugs for most common tumours that metastasize to cally administered immune checkpoint inhibitors the leptomeninges and all of them have a short half- may show efficacy in the near future in controlling life (4–8 h), which is why these drugs have to be ad- leptomeningeal disease of immune-responsive tu- ministered two times per week, at least initially. Other mours such as melanoma, NSCLC, SCLC, renal cell disadvantages are local and sometimes irreversible and triple-negative breast cancer, the drug reservoir toxicities (e.g. arachnoiditis, myelopathy, progressive “CSF” could become an interesting therapeutic niche. leukoencephalopathy). Further pharmacokinetic studies will have to show In recent years, some monoclonal antibodies have whether intrathecal antibody therapy alone may sub- been successfully administered intrathecally and pre- stitute for systemic administration. liminary experience has been gathered in phase I studies, small case series and individual observations. Activity of intrathecally administered monoclonal an- tibodies in the three compartments “cerebrospinal 194 Leptomeningeal metastases from solid tumours K short review in patients with treated, asymptomatic brain metas- Systemic therapies tases [20]. Few specific data are available for leptomeningeal dis- A post hoc exploratory subgroup analysis of the ease and systemic therapy; most have been extrapo- KAMILLA trial in 398 anti-HER-2 pretreated patients lated from patients with brain metastases or advanced with asymptomatic BM represents the largest cohort disease. treated with T-DM1. A clinical significant benefit was Classical chemotherapy has been used for lep- observed in patients with and without prior radiother- tomeningeal disease and some have proven to be apy [21]. Combination strategies with immunother- active in sensitive tumours, among others, 5-fluo- apy are worth exploring, as T-DM1 treatment seems rouracil, capecitabine, pemetrexed cisplatin, carbo- effective in increasing the presence of TILs [22]. platin, vinorelbine, gemcitabine, high-dose methotrex- A non-randomized phase II study with the CNS- ate (≥3g/m ), thiotepa, high-dose cytarabine, etopo- penetrant CDK4 inhibitor abemaciclib for hormone side, eribulin. receptor-positive breast cancer patients with brain The anti-HER-2 monoclonal antibodies trastuzumab and leptomeningeal metastases did not meet its pri- and pertuzumab have in general modest activity mary endpoint (intracranial response rate, iORR), when administered as monotherapy in metastatic but an intracranial clinical benefit rate (iCBR) was de- HER-2-positive disease and they do not cross an in- scribed for the cohort with highly pretreated hormone tact blood–brain barrier. Concomitant chemotherapy receptor-positive, HER-2-negative breast cancer pa- administration is needed for optimal extracranial ac- tients. iCBR in the study was defined as CR, PR or SD tivity. In addition, there is statistically and clinically ≥ 6 months. Fourteen out of 55 patients of cohort A significant improved response and time to progres- (hormone-receptor-positive, HER-2-negative) had an sion for the continuation of trastuzumab beyond iPR or iSD > 6 months, resulting in an iCBR of 24.1%. progression in the management of women with HER- [23]. 2-positive advanced breast cancer [18] and it has been Activity of anti-hormonal drugs, such as tamox- suggested that an improvement of systemic disease ifen or aromatase inhibitors, has been reported in the control delays the onset of brain metastasis (BM), as brain and in the leptomeninges and could potentially has been demonstrated in the CLEOPATRA trial [19]. be considered in responsive tumours [24]. Similar observations are reported for the anti- Next generation targeted tyrosine kinase inhibitors HER-2 antibody-drug conjugate ado-trastuzumab (TKI) with small molecular weight (400–500 D), low or emtansine (T-DM1) where the chemotherapy back- lacking dependence on efflux transporters (e.g. P-gly- bone has been directly linked to the antibody, allowing coprotein, Pgp)—not a sole criterion though—have targeted tumour delivery of an otherwise toxic com- been reported to have clinically meaningful activity pound, DM1, a potent microtubule polymerization in the CNS and may even have preventive potential inhibitor. on the formation of new LM or brain metastases in T-DM1 activity in central nervous system metasta- tumours with corresponding actionable targets. sis was assessed in a retrospective, exploratory analy- Examples are osimertinib for EGFRmut, alectinib sis of the EMILIA randomized phase III trial, compar- for ALK- and RET-, lorlatinib for ALK—and ROS 1 and ing safety and efficacy of T-DM1 with standard of care, brigatinib for EGFR-, ALK- and ROS1-altered NSCLC, capecitabine and lapatinib. In participants who had but also vemurafenib or dabrafenib with and with- been previously treated with trastuzumab and a tax- out MEK-inhibitors for BRAFV600Emut tumours (Ta- ane, the analysis suggested that T-DM1 may confer ble 1). They have all shown to result in impressive a survival advantage over capecitabine and lapatinib and often durable intracranial responses [25]. Exem- Table 1 Selected molecular targeted agents for LM from NSCLC (adapted from [25]) Drug Target MW Substrate for efflux transport CNS penetration (CSF/plasma or CSF/blood) Erlotinib EGFR 393 Yes 2.8% to 3.3% Gefitinib EGFR 447 Yes 1.13% Afatinib EGFR 486 Yes 1.65% Osimertinib EGFR (T790M) 500 Yes 2.5% to 16% Zorifertinib EGFR 460 No 100% Crizotinib ALK, MET, ROS1 450 Yes 0.26% Ceritinib ALK, ROS1 558 Yes 15% Alectinib ALK, RET 483 No 63% to 94% Brigatinib ALK, ROS1, EGFR 529 Yes no data Lorlatinib ALK, ROS1 406 Yes, but low 31% to 96% Vemurafenib BRAF 490 Yes 0.98% LM leptomeningeal metastases, NSCLC non-small cell lung cancer, MW molecular weight K Leptomeningeal metastases from solid tumours 195 short review plary, in ALK-TKI refractory NSCLC patients with LM, is a heterogeneous uptake into the leptomeninges, the intracranial ORR, intracranial disease control rate, which may explain, at least in part, their limited effi- median duration of treatment and median PFS were cacy. Some patients may benefit from systemic treat- 45% and 91%, 5.3 months, and 9.3 months respec- ment beyond progression in the CNS if they are of- tively [26]. A higher incidence of LM was observed in fered local treatment for their intracranial disease. For NSCLC patients harbouring EGFR mutations after an all these considerations, the neurological and general effective EGFR TKI treatment. In particular, mutation condition and the patient’s wish must be taken into L858R potentially predicts a higher risk of LM com- account in a difficult-to-treat disease manifestation pared with deletion of exon 19. These results highlight with still poor outcome. the importance of determining the current mutational status, preferentially from liquid biopsies of the CSF Future directions [25, 27]. Lapatinib is effective to a lesser extent for HER- The CSF space is a challenging niche for metastatic 2-positive tumours due to its dependence on the tumour cells. Recent research focused on the bio- Pgp. Tucatinib, a highly selective TKI against HER-2, chemical composition of the CSF in the setting of has reported activity in 75 untreated patients with leptomeningeal metastases. Mechanisms of cell sur- HER-2-positive brain metastases in combination with vival and distinct gene expression signatures were dis- trastuzumab and capecitabine; intracranial ORR of covered. Some appear to act via a high-affinity iron 47.3% could be reached in the HER2CLIMB trial [28]. transport system to maintain iron-dependent cellu- While the current evidence on the activity of TKIs lar survival functions and the suppression of local comes from case series and retrospective studies with macrophage activation by iron deprivation. Whether LM, prospectively collected data are becoming avail- this iron-capturing system also confers increased sur- able in rapid succession. vival of circulating tumour cells requires further in- Immune checkpoint inhibitors (IO) have been vestigations [32]. shown to be effective in the brain by exerting activity Cell-free circulating tumour DNA (ctDNA) in the on BM and LM indirectly by T cell responses [29, 30] CSF holds useful information regarding diagnosis to and thus might even have prophylactic potential, as better characterize LM, detect actionable genomic al- has been suggested by a lower incidence of new BM terations and monitor responses to therapy [33]. with durvalumab in NSCLC [31]. Combining IO with RT might further augment the efficacy (Table 2). Take Home Message Leptomeningeal metastases should be treated ac- Concluding remarks cording to the clinical, MRI and cytological presen- For leptomeningeal disease intrathecal therapy seems tation, taking into consideration the general and particularly useful when targeted drugs with a long neurological status, molecular characteristics, other half-life are available, e.g. trastuzumab. Systemic metastatic sites and prior treatments. therapies with the ability to overcome brain barriers  Promising approaches are under development and are only effective if tumour cells are sensitive. A com- trials should be conducted specifically for this patient mon feature of all systemically administered drugs population. Funding OpenAccessfundingprovidedbyUniversitätZürich. Table 2 Drugs most commonly used for leptomeningeal Conflict of interest E. Le Rhun has received honoraria for disease from solid tumours lectures or advisory board participation or consulting from Intrathecal drugs Abbvie, Adastra, Daiichi Sankyo, Tocagen, Leo Pharma and Methotrexate, Initially 2 ×/week Seattle Genetics. S. Hofer declares that she has no competing 10–15 mg interests. Thiotepa, 10 mg Initially 2 ×/week Open Access This article is licensed under a Creative Com- Trastuzumab, 150 mg Weekly to three weekly mons Attribution 4.0 International License, which permits Systemic drugs use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit Next generation TKI According to target, taking into account resistance to the original author(s) and the source, provide a link to mechanisms the Creative Commons licence, and indicate if changes were Chemotherapeutic According to sensitivity or resistance of the tumour made. 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Journal

memo - Magazine of European Medical Oncology – Springer Journals

Published: Jun 1, 2021

Keywords: oncology; medicine/public health, general

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