Leptomeningealmetastases:

standards of careEmilie Le Rhun

Lille, France

Disclosures

ELR has received research grants from Mundipharma and Amgen and honoraria for lectures or advisory board participation from Abbvie, Daiichi Sankyo, Mundipharma and Novartis.

Definition of LM• LM is defined as the spread of tumor cells within the leptomeninges and the

subarachnoid space• LM is synonymous with neoplastic meningitis and can be further denoted by

primary tumor as leptomeningeal carcinomatosis, gliomatosis or lymphomatosis

Invasive lobularcarcinomaMGG X40

Axial braingadolinium enhanced MRI

Sagittal spinal gadolinium enhanced MRI

Lumbar puncture

Background• Leptomeningeal metastasis (LM) affects up to 10%

of patients with solid tumors

• The median survival is limited to 2-3 months, witha 1-year survival rate below 10%

• Only a few prospective clinical trials are available

• Treatment strategies include intra-CSF chemotherapy, systemic pharmacotherapy, and focal or large volume radiotherapy and vary widelyacross centers

Epidemiology• LM occurs:- in the context of progressive systemic disease in approximately 70%- in around 20% at the time of first progression after initial treatment - in up to 10% at the time of cancer diagnosis

• In recent large cohorts of LM patients, brain metastases were associated with LM in 33%-54% of breast cancer, 56%-82% of lung cancer, and 87%-96% of melanoma patients

• Risk factors :- in all patients: opening of the ventricular system during brain metastases

surgery or resection of cerebellar metastases, especially when using a piece-meal resection

- in breast cancer patients: lobular subtype and triple-negative tumours - in lung cancer patients: EGFR-mutant and ALK-positive tumors- in melanoma patients: no risk factors identified

Levels of evidence in LM

No standards for:• Neurological examination• Neuro-imaging assessment• CSF diagnosis

• No trial on systemic treatment• No trial on radiotherapy• Only 5 trials on intra-CSF therapy….

Clinical evaluation

• Typical clinical features include: headache, nausea and vomiting, mental changes, gait difficulties , cranial nerve palsies with diplopia, visual disturbances, hearing loss, sensorimotor deficits of extremities, cauda equina syndrome, radicular, neck and back pain

Standardized neurological evaluationthat needs validation

LANO grid, Chamberlain et al., 2016

Imaging evaluationSlice thickness 1 mm or less Gadolinium injected 10 min before data acquisition (EANO ESMO) at a dose of 0.1 mmol/kg Standardized and validated gridFollow-up on the same deviceMRI prior to lumbar puncture

EANO ESMOBrain axial, coronal and sagittal T1 without

and with contrast enhancement, axial T2, axial and coronal FLAIR

Spine sagittal T2 and T1 without and with contrast

Imaging subtypesType A: LM with typical linear MRI abnormalities

Type B: LM with nodular disease only as type B

Type D: LM without MRI abnormalities, except possibly hydrocephalus

Type C: LM with both linear and nodular disease

CSF flow studies

for patients who are candidates for intra-CSF pharmacotherapy and in whom CSF flow obstruction may be present:• hydrocephalus, • large nodules potentially reducing the CSF

circulation on MRI, • unexpected toxicity of intra-CSF treatment.

CSF analysis

Specificity >95%Sensitivity: first lumbar puncture: 55%

second lumbar puncture: 80%In recent large cohorts of LM patients, CSF cytology was considered positive in 66%-90%.

Invasive Lobular Carcinoma- MGG X40

Melanoma - MGG X40

CSF analysis

EANO ESMOTechnical aspects - fresh CSF samples processed within 30

minutes after sampling; alternatively, freshCSF samples fixed with Ethanol-Carbowax

- CSF volume > 10 ml (at least 5 ml)

- routine stainings: Papanicolaou and Giemsa; additional immunocytochemical stainings (uponindication and availability of material) - a second CSF sample should be analyzed if the initial CSF sample is negative for diagnosis

Interpretation of the results

- positive (presence of tumor cells) - equivocal (suspicious or atypical cells) - negative (absence of tumor cells)

In presence of tumor cells, the diagnosis is confirmed (type I)In other cases the diagnosis can only be probable or possible (type II)

Diagnosis• Typical clinical features include: headache, nausea and vomiting, mental changes,

gait difficulties , cranial nerve palsies with diplopia, visual disturbances, hearing loss, sensorimotor deficits of extremities, cauda equina syndrome, radicular, neck and back pain

• MRI features:linear leptomeningeal disease (type A) nodular leptomeningeal disease (type B) both (type C) no neuroimaging evidence of LM except possibly hydrocephalus (type D)

• CSF cytology: positive, equivocal, negativethe diagnosis can be confirmed by cytology (or histology) (type I) or not (type II)

Based on these considerations, the likelihood of LM can be assigned “confirmed”, “probable”, “possible” or “no evidence for”

Classification of LM:The EANO ESMO Proposal

Cytology/

biopsy

MRI Confirmed Probable* Possible* Lack of

evidenceType I:positive CSF cytology or biopsy

IA + Linear + n.a. n.a. n.a.

IB + Nodular + n.a. n.a. n.a.

IC + Linear +

nodular

+ n.a. n.a. n.a.

ID + Normal + n.a. n.a. n.a.

Type II:clinical findings and neuroimaging only

IIA - or

equivocal

Linear n.a.** With typical

clinical signs

Without typical

clinical signs

n.a.

IIB - or

equivocal

Nodular n.a. With typical

clinical signs

Without typical

clinical signs

n.a.

IIC - or

equivocal

Linear +

nodular

n.a. With typical

clinical signs

Without typical

clinical signs

n.a.

IID - or

equivocal

Normal n.a. n.a. With typical

clinical signs

Without typical

clinical signs

*requires a history of cancer; **not applicable

Prognosis

Median OSwithout tumour-specific treatment 6-8 weeks Breast cancer with treatment 1.75-4.5 months Lung cancer with treatment 3-6 months Melanoma with treatment 1.7-2.5 months

Chamberlain 2009, Groves 2010, Grossman 1982, De Angelis 1998 , Gauthier 2010, Rudnicka 2007, Clatot 2009, De Azevedo 2011, Le Rhun 2013, Harstad 2008, Papadopoulos 2002, Geukes Foppen 2016, Grossman 1999 , Hammerer 2005, Morris 2011, Park 2011, Gwak2013, Lee 2013, Kuiper 2015

Prognostic factors• performance status at diagnosis of LM • primary tumour type• cerebrospinal fluid (CSF) protein levels• administration of combined modality treatment, systemic

treatment, or intra-CSF treatment• initial clinical or CSF responses to treatment

(Rudnicka 2007, Gauthier 2010, Lee 2011, de Azevedo 2011, Niwinska 2013, Yust Katz 2013, Le Rhun 2013, Clarke 2010, Oechsle 2010, Herrlinger 2004, Clatot 2009, Hyun 2016)

An association of WBRT with overall survival has not been consistently reported.

(Morris 2012, Park 2012, Gwak 2013, Abouharb 2014)

224 participants between April 7 and August 8, 2016

Randomized trials assessing the response to intra-CSF treatment in LM

Trial Design Population Primary endpoint Efficacy Safety

Grossman

1993

IT MTX versus IT

thiotepa

Solid tumors (n=40),

CUPS (n=1) and

lymphomas (n=10)

Neurological response

rate

IT MTX vs. IT thiotepa

Neurological response rate: none

Neurological stabilization: 32% vs. 12.5%

Survival: 15.9 weeks vs. 14.1 weeks

IT MTX vs. IT thiotepa

Serious toxicities similar in both group

Mucositis (p=0.04) and neurological complications (p=0.008)

more frequent in MTX armHitchins 1997 IT MTX versus IT MTX

+ cytarabine

Solid tumors (n= 30),

cancers of unknown

primaries (n=7) and

lymphomas (n=7)

Response rate IT MTX vs. MTX + cytarabine

Response rate : 61 vs. 45% (p

Neuroimaging was not used to evaluate the neurologicalresponse; trial stopped after 35 patients enrolled between1991 and 1998 (instead of 50 initially expected)

Median survival: 18.3 (SE 6.7) weeks in the intra-CSF arm vs. 30.3 (SE 10.9) weeksin the control arm

Breast cancer patients; diagnosis of LM based on CSF cytology or MRI, no progressive or untreated brainmetastases

Intraventricular MTX, appropriate systemic therapy, and if necessary RT to clinically relevant sites

Appropriate systemic therapy, and if necessary RT to clinically relevant sites – No intraCSF therapy

Deposein trial (NCT01645839)

Main inclusion criteria• Adult breast cancer patients requiring a systemic treatment at inclusion, ECOG PS: 0-2• Diagnosed with LM (CSF positive cytology; combination of typical clinical and MRI findings)• Meningeal metastases 0.5 if treated by SRS/SRT)• Asymptomatic brain metastases permitted• WBRT not allowed• Untreated CSF blockade not allowed

Main objective

• To compare the neurological progression free survival (clinical and imaging criteria) between the 2 groups

Liposomal cytarabine until unacceptable toxicity, neurological progression or a max of 12 monthsSystemic treatment at the discretion of the investigator

Group ABC patients with LMand inclusion criteria

Systemic treatment alone

Group B Systemic treatment+ liposomal cytarabine

R

Intra-CSF therapyLimits of intra-CSF therapy In favor of intra-CSF therapyNo randomized trial has demonstrated that intra-CSF therapy prolongs survival in LM patients

Used by a large majority of physicians in addition to systemic treatments across Europe (only 11% ofphysicians never use intra-CSF therapy)

Recent prospective safety data have shown a good tolerance of liposomal cytarabine

The compounds routinely used for intra-CSF treatment do not have a key role as single agents for systemic treatment of common cancers causing LM

Compounds with systemic efficacy are currentlyunder evaluation as intra-CSF agents in clinical trials

Intra-CSF therapy has only a limited penetration (1-3 mm) into solid tumor lesions

Intra-CSF therapy may be inefficient and toxic in case of CSF flow blocks

Rationale for the treatment of floating tumor cells in the CSF in the setting of little or no blood CSF barrierdysfunction

Rationale for the treatment of linear diffuse or ependymal spread not yet accompanied by bloodbrain barrier dysfunction

Is there a role for intra-CSF treatment?in selected patients:

In the presence of: - floating tumor cells in the CSF in the setting of little or

no blood CSF barrier dysfunction- linear diffuse or ependymal spread not yet

accompanied by blood brain barrier dysfunction

Not as first option in patients with symptomatichydrocephalus who require ventriculoperitoneal shunt placement or with a ventricular device without on/off option

Route of administration of intra-CSF therapy

• Advantages of the ventricular route:

- certainty that the drug is not delivered into the epidural or subdural space

- more uniform distribution of the agent

- more patient comfort, faster procedure, which improves compliance and safety of drug administration

• Safety of ventricular devices shown in several cohorts of patients using different technologies and several devices (

Systemic pharmacotherapy

• a priori no reason to believe that systemic pharmacotherapy for contrast-enhancing manifestations of LM should be less efficient than for other systemic manifestations of cancer

• increased CSF protein levels in most LM patients confirm that the blood-CSF barrier is commonly disrupted in LM

• no specific prospective trials reported on systemic treatment of LM, but retrospective series suggest some activity of systemic chemotherapy

• the best systemic treatment for LM is determined by:- the primary tumour, - its molecular characteristics or the molecular characteristics of tumour cells

of the CSF when available - and prior treatment of the underlying malignancy.

Radiotherapy• No randomized clinical trial to assess the efficacy and tolerance of

RT in LM has been conducted.

• Focal RT (involved-field or stereotactic RT or radiosurgery) can be used to treat nodular disease and symptomatic cerebral or spinal sites.

• WBRT may be considered for extensive nodular or symptomatic linear LM or co-existing brain metastases.

• Cerebrospinal RT is rarely an option for adult patients with LM from solid cancers because of risk of bone marrow toxicity, enteritis and mucositis, and the usual co-existence of systemic disease.

Supportive care• When required clinically, the lowest dose of steroids

should be used for the shortest time possible.

• Seizures should be managed using drugs that do not interact with systemic treatments. Primary prophylaxis is not recommended.

• Ventriculoperitoneal shunting may provide durable relief from symptomatic hydrocephalus

Life expectancy < 1 month

Palliative approach

CSF cytology positive

Type I LMpositive CSF or biopsy

Type II LMclinical findings and neuroimaging only

Life expectancy ≥ 1 month

Active BMNo active BM

CSF cytology negative(LM confirmed by biopsy)

Type IIA• IT therapy (+)• Modification of

systemictherapy or WBRT +

Type IIB• IT therapy -• Modification of

systemictherapy (+)

• Focal RT +

Type IIC• IT therapy (+)• Modification of

systemic therapy +

• WBRT and/or Focal RT +

Type IIA• IT therapy (+)• Modification of

systemictherapy +

• WBRT (+)

Type IIB• IT therapy -• Modification of

systemictherapy +

• Focal RT +

Type IIC• IT therapy (+)• Modification of

systemictherapy +

• WBRT and/or Focal RT +

Type IIA • IT therapy (+)• Modification of

systemictherapy or WBRT or both +

Type IIB• IT therapy -• Modification of

systemictherapy +

• Focal RT +

Type IIC• IT therapy (+)• Modification of

systemictherapy +

• WBRT and/or Focal RT +

Type IIA • IT therapy (+)• Modification of

systemictherapy +

• WBRT (+)

Type IIB• IT therapy -• Modification of

systemictherapy +

• Focal RT (+)

Type IIC• IT therapy (+)• Modification of

systemictherapy +

• WBRT and/or Focal RT (+)

No active BM

Stable ECD

Progressive ECD

Type IA• IT therapy +• Modification of

systemictherapy (+)

• WBRT (+)

Type IB• IT therapy +• Modification of

systemictherapy (+)

• Focal RT +

Type IC• IT therapy +• Modification of

systemictherapy (+)

• Focal RT +, WBRT (+)

Type ID• IT therapy +• Modification of

systemictherapy (+)

• RT-

Type IA• IT therapy +• Modification of

systemictherapy +

• WBRT (+)

Type IB• IT therapy +• Modification of

systemictherapy +

• Focal RT (+)

Type IC• IT therapy +• Modification of

systemictherapy +

• WBRT or SRT (+)

Type ID• IT therapy +• Modification of

systemictherapy +

• RT -

Type IA• IT therapy +• Modification of

systemictherapy or WBRT or both +

Type IB• IT therapy +• Modification of

systemictherapy +

• Focal RT +

Type IC• IT therapy +• Modification of

systemictherapy +

• WBRT and/or Focal RT +

Type ID• IT therapy +• WBRT and/or

modification of systemictherapy +

Type IA• IT therapy +• Modification of

systemictherapy +

• WBRT (+)

Type IB• IT therapy +• Modification of

systemictherapy +

• Focal RT (+)

Type IC• IT therapy +• Modification of

systemictherapy +

• WBRT and/or Focal RT (+)

Type ID• IT therapy +• Modification of

systemictherapy +

• WBRT (+)

Active BM

Stable ECD

Progressive ECD

Stable ECD

Stable ECD

Progressive ECD

Progressive ECD

Follow-up of LM

EANO ESMO Neurological assessment: standardized gridCerebrospinal MRI: LANO gridCSF cytology: positive, negative, equivocal

Evaluation every 2-3 months

Response Assessment

EANO ESMOResponse Clinically improved or stable

Neuroimaging improved

CSF cytology improved or stableStable Clinically stable

Neuroimaging stable

CSF cytology stableSuspicion of

progression

Clinically worse, neuroimaging stable, CSF cytology stable

or

Clinically stable or worse, neuroimaging stable, CSF cytology worse

(increased tumour cell counts)Progression Neuroimaging worse

or

de novo positive CSF cytology

Conclusions

• Different subtypes of LM should be considered according to the results of cytology and cerebrospinal MRI

• Management strategies for individual patients should be derived by integrating:

- general and neurological health status- CSF findings - neuroimaging findings - absence or presence of solid brain and systemic metastases - histology and molecular status of the primary tumor- previous treatments

• A standardized follow-up should be considered

Leptomeningeal metastases:�standards of careDisclosuresDefinition of LMBackgroundEpidemiologyLevels of evidence in LMSlide Number 7Clinical evaluationImaging evaluationImaging subtypesCSF flow studiesCSF analysisCSF analysisDiagnosisClassification of LM:�The EANO ESMO ProposalPrognosisPrognostic factorsSlide Number 18Randomized trials assessing the response to intra-CSF treatment in LM Slide Number 20Deposein trial (NCT01645839) Intra-CSF therapyIs there a role for intra-CSF treatment?Route of administration of intra-CSF therapySlide Number 25Systemic pharmacotherapyRadiotherapySupportive careSlide Number 29Follow-up of LMSlide Number 31Conclusions