METASTATIC DISEASES OF NERVOUS SYSTEM

METASTATIC DISEASES OF NERVOUS SYSTEMDR. SUMIT S. KAMBLESR NEUROLOGYGMC, KOTA

BRAIN METASTASISMost common intracranial tumors in adults.

Accounting for more than one-half of brain tumors.

Incidence of brain metastases increasing, due to both improved detection of small metastases by MRI and better control of extracerebral disease resulting from improved systemic therapy

Common causes of brain metastases in adults with their approximate frequency are:

Lung 50 percent Breast 15 to 20 percent Unknown primary - 10 percent Melanoma 10 percent Colon and rectum - 5 percent

Distribution of metastases roughly follows the relative weight of and blood flow to each area.

Cerebral hemispheres 80 percent Cerebellum 15 percent Brain stem 5 percent

SYMPTOMS OF BRAIN METASTASES Symptom Patients % Headache42 Focal weakness 27 Cognitive dysfunction 31 Seizure 20 Gait ataxia 17 Sensory disturbance 6 Speech problems 10

Imaging StudiesContrast-enhanced MRI is preferred imaging study Radiographic features that can help differentiate brain metastases from other CNS lesions include:Presence of multiple lesionsLocalization at the junction of the grey and white matterCircumscribed marginsLarge amounts of vasogenic edema compared to the size of the lesion

MRIT1typically iso to hypointenseif haemorrhagic may have intrinsic high signalnon-haemorrhagic melanoma metastases can also have intrinsic high signal due to the paramagnetic properties of melaninT1C+enhancement pattern can be uniform, punctate, orring-enhancing, but it is usually intensedelayed sequences may show additional lesions, therefore contrast-enhanced MR is the current standard for small metastases detectionT2typically hyperintenseFLAIR:typically hyperintense with hyperintense peri-tumoural oedema

MR spectroscopyintratumoural choline peak with no choline elevation in the peritumoural oedemaany tumour necrosis results in a lipid peakNAA depletedDWI:oedema is out of proportion with tumour size and appears dark on trace-weighted DWI

Nuclear medicineFDG PETConsidered the best imaging tool for metastases.Only detect mets up to 1.5 cm in size, therefore contrast MRI remains the gold standard to rule out small mets.

Radiographic Features of Brain Metastases

Overveiw of ManagementSpecific treatments directed against the brain metastasesManagement or prevention of complications (eg, seizures, cerebral edema, prevention of deep venous thrombosis)Treatment of systemic malignancy if appropriate

Prognostic ClassificationRecursive Partitioning Analysis (RPA)Parameters that determine survival are: Performance status The extent of extracranial disease Age Primary diagnosis

Recursive Partitioning Analysis (RPA)Recursive Partitioning AnalysisClass IClass IIClass IIIKarnofsky performance score 70 or higher Age < 65Controlled primary tumorWithout extracranial metastases Median survival was 7.1 months. These patients are considered to have a favorable prognosis.Karnofsky performance score 70 or higherAge > 65Uncontrolled primary tumorOther extracranial metastases

Median survival in this group was 4.2 months.Karnofsky performance score less than 70

Median survival of 2.3 months. This group is considered to have a poor prognosis.

Management of Brain mets based on RPAPatients having a favorable prognosis - treatment focuses on the eradication or control of the brain metastases. Includes surgical resection and various forms of radiation therapy (eg, whole brain, stereotactic radiosurgery).

Patients having a poor prognosis- treatment focuses on control of symptoms caused by the brain metastases, as well as maintenance of neurologic function to as great an extent as possible.

Various modalities : 1.WBRT

2.SRS(STEREOTACTIC RADIOSURGERY)

3.SURGERY

4. SUPPORTIVE CARE WITH DEXAMETHASONE

Symptom ManagementControl of peritumoral edema and increased intracranial pressure with corticosteroidsTreatment and prevention of seizuresManagement and prevention of venous thromboembolic disease

Control of Vasogenic EdemaDexamethasone is the standard agent: relative lack of mineralocorticoid activity reduces the potential for fluid retention. dexamethasone associated with a lower risk of infection and cognitive impairment compared to other glucocorticoids

Dose and scheduleDexamethasone regimen consists of a 10 mg loading dose, followed by 4 mg four times per day or 8 mg twice daily.

Treatment and Prevention of SeizuresPatients who have one or more seizures associated with a primary or metastatic brain tumor, initial treatment with a single agent antiepileptic drug (AED) (Grade 1A)

Patients without a history of seizures and who have not undergone a neurosurgical procedure, recommend NOT using prophylactic AEDs (Grade 1B)

Management and Prevention of Venous Thromboembolic Disease

Treatment of venous thromboembolism

Anticoagulation in all patients with brain tumors and venous thromboembolism (VTE) except those that have a high rate of intracranial hemorrhage (ie, metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma)VTE in low-grade glioma and benign tumors should be treated for three to six months. Long-term anticoagulation is recommended for malignant gliomas.

LMW heparin rather than warfarin for anticoagulation Prophylaxis of VTEPatients undergoing surgery, use pneumatic compression stockings combined with postoperative LMW heparin or unfractionated heparin beginning 12 to 24 hours after surgery and continuing until ambulation is resumed.

SPINAL METASTASISSpine most common site for skeletal metastases

Metastatic lesions are most common tumors of the spine (95-98%) 5-10% of the patients with cancer develop spine metastases*All age groups with highest age incidence in between 40 and 65 yearsMale:Female 3:2

Vertebral body affected first

Approximately 70% of patients who die of cancer have evidence of vertebral metastases on autopsy

PathophysiologyHematogenous Spread:Batsons plexusArterial embolization

Direct invasion

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Primary Sites

Breast (30.2%)Lung (20.3%)Blood (10.2%)Prostate (9.6%)Urinary tract (4%)

Skin (3.1%)Unknown 1 (2.9%)Colon (1.6%)Other (18.1%)

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Level of MetastasesThoracic 70%

Lumbar 20%

Cervical 10% Basis of anatomic locationIntradural - 5%IntramedullaryExtramedullary Extradural - 95%Pure epidural rareArising from the vertebrae - most frequent

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Clinical PresentationPain (85%)Biologic: local release of cytokines, periosteal irritation, stimulation of intraosseous nerves, increased pressure or mass effect from tumor tissue in the bone Mechanical: nerve compression, pathologic fractures, instability

Weakness (34%)Spinal cord compression in 20%Early: edema, venous congestion, and demyelinationLate: secondary vascular injury and spinal infarction

Mass (13%)

Constitutional Symptoms

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EvaluationHistoryPhysical ExamLaboratory: CBC, ESR, CRP, LFT, BUN, CreatinineCa, PO4, Alk PhosphataseUrinalysis: routine, Bence-Jones ProteinsSpecial: PSA, thyroid Function test, serum and urine protein electrophoresis, liver function tests, stool guaiac, CEA

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Imaging

Plain x-ray- Bone mets can be purely lytic, blastic ,mixed i. Lytic - lung, kidney, breast, GIT, melanoma ii Blastic prostate , bronch.carcinoids, bladder, stomach iii. Mixed breast ,lung, GIT

X-ray of spine: AP, lateral, obliquewinking owl sign: pedicle destructionVertebral body destruction is not visible until 30-50% of trabeculae are involvedNegative x-ray does not rule out tumor

Bone scan Superior sensitivity Extent of dissemination Define the most accessible lesion to biopsy in cases of unknown primary

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MAGNETIC RESONANCE IMAGINGSuperior sensitivity and specificityMethod of choice to evaluate spine Define the intramedullary, intradural and extramedullary lesions Extent of the lesion Differentiation from other pathologies such as infection and osteoporotic Fat suppression and Gadolinium enhancement to improve the delineationHypointense T1 , hyperintense in T2 and gadolinium enhanced T1

BiopsyIndicated if diagnosis is unclear after workup

Options:CT-guided: most accessible lesion, minimal morbidity, tattoo tract for later excisionAccuracy: 93% for lytic lesions, 76% for sclerotic lesions

Open: cost, delay, definitive for benign tumors

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PER CUTANEOUS APPROACHES FOR BIOPSY

Posterior cervicalC 1 3= TransoralSub axial cervicalAnterior or posterior to sternocleidomastoidThoracic and LumbarTranspedicular or Postero lateral SacralPosterolateral

ManagementGeneral MxMedical Mx / Radiotherapy MxSurgical MxPain Mx

General MxAnemia SteroidsNutritional StatusHydrational statusSupplements

Medical Mxi.Chemotherapyii.Hormonaliii Biphosphonate

Chemotherapy Given as therapeutic and palliative treatment especially in Breast , lung , Renal cell ca.

Hormonal- Breast , prostate and endometrial ca.Endocrine dependant organs.

Biphosphonate

Inhibit osteoclast-mediated resorptionInduce osteoclast apoptosisStandard treatment in hypercalcemia in malignancy Reduces metastatic bone pain esp. clodronate and pamidronateRecalcification

RadiotherapyPain relief mode of action not really understood reduces tumour bulk, reduces pain mediator (PG)releasing cellsPost fixation irradiationPrevention of spinal cord compression-recent vertebral collapsePts with contraindication for surgery

External Beam Radiotherapy (EBRT)RadiosensitivityMyeloma & Lymphoma: most radiosensitiveProstate, Breast, Lung and Colon: moderatelyThyroid, Kidney, Melanoma: not radiosensitive

Dose5,000 cGy in 25 fractions over 5 weeks (C & L-spine)4,500 cGy over 4 -5 weeks in T-spine

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Surgical MxMostly PalliativeIndications

Spinal instability

Spinal compression secondary to retropulsed bones or spinal deformity

Radiation-resistant tumors (sarcoma, non-small cell lung cancer, colon, renal cell, melanoma)

Failure of radiation (progression during treatment or recurrence)

Intractable pain unresponsive to medical treatment

Unknown primary tumor (histological diagnosis)

Rapid progression of neurological deficits

Goals of SurgeryCorrect and prevent deformity by stabilizing deformityDecompressing neural structuresOpen biopsy if primary unknown

Pre-operative prognostic values/scoring

Score = < 5 dies within 3 months > 9 survives average 12 mthsSurgery = 9 surgical

Category iii grey area , either medical or surgical . - if there is severe epidural cord compression non radiosensistive , needs surgery

Score2-3 wide / marginal for long term survival4-5 marginal/intralesional6-7 palliative surgery for short term palliation8-10 non operative supportive care

Surgical approachAnterior approach - modern eraPredominant area of metastasisDoes not disturb posterior stability in presence of the kyphosis Pain relief in 80 95% of ptsNeurologic improvement in 75% of pts

Post decompressive laminectomy - old era - limited value in regaining neurologic function

LEPTOMENINGIAL METASTASISInvasion of leptomeninges or CSF by cancer is called leptomeningeal metastasis (LM) or neoplastic meningitis.

Clinically diagnosed LM affect ~ 5% of pt with metastatic cancer Autopsy studies the frequency of LM averages 19% of pts with cancer pts. LM is diagnosed in 4-15% of pt with solid tumors5-15% of pt with leukemia and lymphoma1-2% of pt with primary brain tumor

Modes of spread:Hematogenous: most commonEndoneural/perineural: paravertebral tumorsDirectChoroid plexusIatrogenic

Mortality/Morbidity Median survival-7 months for LM from Breast cancers - 4 months for LM from Small cell lung - 3.6 months for LM from Melanomas

Without therapy, survive 4-6 weeks With therapy, most pts die from the systemic complication of their cancer

Signs and symptomsLM classically presents with pleomorphic clinical manisfestations encompassing symptoms and signs in 3 domainsCerebral hemispheres Posterior fossa/Cranial nervesSpinal cord and roots

DIAGNOSISPatients may be diagnosed with LM when one of the following criteria is met:1. Positive CSF cytology2. Positive LM biopsy3. Positive MRI in a pateint with a clinical syndrome compatible with the diagnosis4. Abnormal CSF biochemical markers consistent with LM

MRIHighly sensitive for diagnosis of LM from solid tumors (76-100%)Less sensitive for hematopoieric tumorsSolid tumor MRI positive for LM 88%Hematopoietic tumor MRI positive for LM 48%

Typical MRI findings Leptomeningeal enhancement in LM can be linear but often has irrigularity or nodularityOften visible in the subarachnoid space, cerebellar folia, or cortical surface, and tumor masses, especially at the base of the brain, with or without hydrocephalus

Occasionally, frank LM are not seen on MRI, but bulky subependymal disease or multiple small sulcal metastases suggest the diagnosis.

Figure 2. Post-gadolinium T1-weighted sagittal (A) and coronal (B) images demonstrate diffuse nodular subependymal and leptomeningeal metastases from the patients primary glioblastoma multiforme.

Martin Begemann et al. Neurology 2004;63:E82004 by Lippincott Williams & Wilkins

Figure 2. Post-gadolinium T1-weighted sagittal (A) and coronal (B) images demonstrate diffuse nodular subependymal and leptomeningeal metastases from the patients primary glioblastoma multiforme. Note the thick nodular metastatic leptomeningeal coating of the pituitary infundibulum.

MRI SPINEMRI can show linear enhancement of the entire cord and linear or nodular enhancement of the cauda equina.Occasionally, clumping of nerve roots at the cauda equina suggests the diagnosis if contrast enhancement is not seen.13A spinal tumor may obstruct CSF flow, resulting in hydrocephalus.

Multiple enhancing nodules are scattered along the cauda equina (blue arrows) with extensive leptomeningeal enhancement of the conus (yellow arrows).

CSF ANALYSISCSF analysis is the gold standard.Presence of malignant cells in the CSF is diagnostic of LM. (sensitivite 71% 86% 93% ) Abnormalities include1. increased opening pressure (200 mm of H2O)2. Increased leukocytes (4/mm3)3. elevated protein (50 mg/dL)4. decreased glucose (60 mg/dL)5. positive cytology

CSF CYTOLOGY

TUMOUR MARKERSTumor markers (eg, CEA, PSA, CA-15-3, CA-125, and MART-1 and MAGE-3 in melanoma) may provide evidence for CSF dissemination of disease, even when serial cytological evaluations are negative.Level of tumor markers are compared between CSF and Serum if CSF level greater than 1% of that in the serum is virtually diagnostic of LM.

CSF-IMMUNOHISTOCHEMISTRYCSF- CYTOGENETICSBIOPSY

TREATMENT

POOR RISK PATIENTSPalliative regimen -RT can be useful for relief of symptoms .Analgesics are given for persistent pain.Anticonvulsants should be reserved for patients with seizures (10 to 20 percent of cases) and should not be administered prophylactically.Serotonin reuptake inhibitors or stimulant medications (eg, modafinil, methylphenidate) for depression or fatigue.

GOOD RISK PATIENTSSurgery-Intraventricular catheter and subgaleal reservoirVentriculoperitoneal shuntChemothery Regional SystemicRadiotherapy

NEOPLASTIC PLEXOPATHY1% of patients who have cancer develop plexus involvement.Brachial plexopathy due to neoplastic infiltration in breast or lung cancer; lumbosacral plexopathy in patients with gynecologic cancer, prostate cancer, sarcomas, lymphomas, or colorectal cancer; should be distinguished from radiationinduced plexopathy.Treatment for neoplastic plexopathy includes radiation and pain control.

THANK YOU

ReferencesNervous System Metastases From Systemic Cancer journals.lww.com/continuum/toc/2015Radiotherapeutic and surgical management for newly diagnosed brain metastasis/es: An American Society for Radiation Oncology evidence-based guideline (2012) Leptomeningeal metastases, Cancer treatment and research, Springer 2005UPTODATE.COM