Joydeep ghosh

Introduction.. Incidence:

Symptomatic: 5%

Asymptomatic: 20%

Relative contributions:

breast cancer (12-35%),

lung cancer (10-26%),

melanoma (5-25%),

gastrointestinal cancer (4-14%), and

cancers of unknown primary (1-7%)

Breast cancer risk factors:

ILC

ER/PR negative

TNBC

Why there is a rise?

More effective therapies involving targeted agents having poor BBB penetration

Pathophysiology.. Modes of spread:

Hematogenous: most common

Endoneural/perineural: paravertebral tumors

Direct

Choroid plexus

Iatrogenic

Signs and symptoms Headache

Vomiting

Alteration of sensorium

Cranial nerve palsies

Neck stiffness is seen in < 15% of cases

Seizures: <10%

Imaging.. MRI:

Entire neuraxis

Most sensitive sequence:

Contrast T1W

FLARE

Associated bran inv. : 40%

Should be done before CSF: false positive due to meningeal irritation

Common MRI findings.. subarachnoid and parenchymal enhancing nodules

(10-35%),

diffuse or focal pial enhancement (10-20%).

Sensitivity: 20 – 90%

CT scan: not at all a good choice

CSF flow blocks.. 30-70% pts: at base of skull level

IFRT:

Restores flow in 30% of pts with spinal inv and 50% pts with bran involvement

After reestablishment of CSF flow, the survival of patients with pretreatment CSF flow interruption is similar to patients without flow abnormalities

Diagnosis of CSF flow block:

111Indium-diethylene-triamine pentaacetic or

99Tc macro-aggregated albumin

CSF sensitivity of a first lumbar puncture is estimated at

45-55%, but can be increased to 80% with a second CSF examination

More than 10ml: improves the outcome 3.5ml: 68%

10ml: 98%

Viability: After 30 min: 50%

After 90min: 10%

Use of biomarkers: not yet recommended

Evaluation of response to treatment majority of clinical trials in LM have utilized a

combination of

CSF cytology (conversion from positive to negative) and

clinical response (improved or stable)

to determine success of LM-directed treatment

no agreed upon radiographic criteria

Survival and prognostic factors..

Median OS: 4 – 6wks

With combined treatment: 2 – 3 months

Depends on primary tumor:

breast > lung/melanoma

With TKI for lung: 3 – 4.3 mo

For lung

ECOG status

Number of chemo/type

Response to treatment

Have been associated with better outcomes..

Correlation with type of therpaygiven.. IT chemo: improved OS

WBRT: did not improve OS

In a small group of patients with EGFR mutations, LM, and lung cancer, EGFR inhibitors had an apparent durable benefit for patients with LM and sensitive EGFR mutations

Treatment options.. Surgery

VP shunt

Complications are high:

Infections

Blockage

Misplacement

RT CSI: Not recommended for routine use in adults because:

Most have previous dosages to neuraxis

Bone marrow reserve is less

High incidence of enteritis

IFRT:

Better than CSI

Can be given to involved site: bulky mets/ blockage sites

WBRT:

Good for pallation

Does not improve O , unlike brain mets

Chemotherapy.. IT

Systemic

Not much use in solid tumors

No effect on OS/ PSF

Toxicity is concern: pts are of poor PS: unlikely to tolerate

IT route

Ommaya reservoir

Advantages:

Better drug delivery

Less painful

Survival benefit in one RCT

Drugs.. Mtx:

Twice weekly for 4 weeks

Exact duration: controversial

Conversion rate: 20 – 60%

CR at 1 month: better OS ( 6mo vs 2 mo)

Cytosar

25 – 100mg

Better CSF bioavialbility

Depot prepn is preferred ( once every 2 weeks)

ITMTx vs depot araC

RCT

30 days vs 58 days: neurlogical progression

P < 0.006

No effect on median OS

Triple IT

No advantage in solid tumors

Increased toxicity

RCT:

MTx vs TIT

55 pts

38% vs 14%

19 vs 10 weeks

Huge selections bias: good PS were given TIT

Advances diaziquone (AZQ),

mafosfamide,

nimustine hydrochloride (ACNU),

4-hydroperoxycyclophosphamide

6-mercaptopurine (6-MP)

dacarbazine,and

gemcitabine.

NSCLC. EGFR mutated pts: log lasting effects upto 11 months

Large retrospective series:

US: median survival: 14 monts

Korean series: 19.2 months

Long-lasting meningeal responses have been reported with erlotinib after a prior progression under gefitinib, and vice versa

Bevacizumab.. Intra-CSF bevacizumab is currently being evaluated in

LM.

A pilot study (n = 15) showed that bevacizumabsignificantly decreases CSF VEGF levels over time and resulted in clinical, imaging and CSF responses or stable disease in 54-73% of LM patients.

Intra-CSF bevacizumab has as well been evaluated in a preclinical rabbit model of LM.

Thank you..