Leading substances for brain cancer

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Leading Substances for Brain Tumour

By: SHIVANI CHAUHAN

• Introduction• Definition• Causes of Brain tumor• Types of Brain tumor• Chemotherapy in brain tumor• Leading Substances for Brain tumor

Outlines

Brain tumor

Definition of Brain tumor

A brain tumor is a localized intracranial lesion which

occupies space with the skull and tends to cause a rise

in intracranial pressure.

Causes of Brain Cancer

DNA Damage Radiation Genetics

NF-1 (acoustic neuromas) Li Fraumeni syndrome Tuberous sclerosis (astrocytomas) Multiple endocrine neoplasia type-1(Pituitary

macroadenoma) Infection

HIV

Distribution of Primary CNS Tumors By Histology

I Primary Brain Tumors:

Benign• Pituitary – adenoma, Cranic-pharyngioma• Meningioma• Acoustic neuroma• Dermoid tumor

Malignant:• Glioma• Primary cerebral Lymphoma• Germinoma• Pineoblastoma• Medullablastoma

II Secondary Brain Tumors

• Lung• Breast• GI• Any primary potentially

Chemotherapy

in Brain Tumors

Timing of Chemotherapy Adjuvant

After surgery or radiation Defined number of cycles Aim

Prolong time of recurrence

Recurrence Number of cycles limited by side effects Aim

Improve symptoms, quality of life and slow progression

A BIT of HISTORY….

• Surgery & radiation mainstays of treatment (and still are)• Chemotherapy options• PCV standard of care for many years

• Procarbazine• Carmustine• Vincristine

• Single agent nitrosurea (Lomustine/carmustine) are equivalent

Rationale For The Use Of Chemotherapy in Neuro-Oncology 1 gram of tumor = one billion cells GTR = removal of 99% (990,000,000 cells) Still have 10,000,000 tumor cells Radiation may remove 99% (9,900,000

cells), leaving 100,000 cells

Barriers to Use of Chemotherapy

Uncommon (2% of all malignancies) Blood-brain barrier Interaction of chemotherapeutic agents with EIAC

Solutions to Barriers to Use of Chemotherapy

Lipophilic molecules (Nitrosureas) Small molecules (Gefitinib) Osmotic Blood Brain Barrier Disruption Design drugs that do not interfere with

EIAC medications Make chemotherapy drugs very expensive

How to overcome BBB ??Newer delivery method includes:

Interstitial chemotherapy uses disc-shaped polymer wafers (known as Gliadel wafers) soaked with carmustine, the standard chemotherapeutic drug for brain cancer.

Intrathecal chemotherapy delivers chemotherapeutic drugs directly into the spinal fluid

Intra-arterial chemotherapy delivers high-dose chemotherapy into arteries in the brain using tiny catheters.

Convection-enhanced delivery (CED) involves placing catheters into the brain tumor or nearby brain tissue to deliver slowly and continuously a cancer drug over several days.

Chemotherapeutic Agents Carmustine (BCNU) Lomustine (CCNU) Procarbazine Temozolomide Vincristine Camptothecans (Irinotecan, Edotecarin) Gefitinib

Carmustine and Lomustine

Highly lipophilic nitrosureas Hydrolysis in vivo to form reactive metabolites Metabolites cause alkylation and cross-linking of DNA CSF equilibrates within one hour to > 50% of plasma

levels Metabolism = hepatic microsomal enzyme Excretion = predominantly renal

Nitrosurea Toxicities

Dose limiting toxicity is myelosuppression Nadir 25-60 days, recovery 35-85 days Nausea and vomiting Dizziness, ataxia, lethargy, disorientation Pulmonary fibrosis (dose dependent) Infertility and mutagenesis Carmustine is a vesicant

Procarbazine

Multiple sites of action (inhibits DNA, RNA and protein synthesis)

Rapid equilibration with CSF Metabolism = microsomal enzymes Excretion = predominately renal

Procarbazine Toxicities

DLT = myelosuppression, nadir 14-21 days, recovery 28 days

Nausea and vomiting CNS depression, lethargy, peripheral neuropathy Hypersensitivity pneumonitis Infertility, mutagenesis Radiation enhancer

Standard ones include:Temozolomide Taken oral First approved in 1999 for adult patients with anaplastic astrocytoma

that did not respond to other treatments. In 2005, it was approved for use during and after radiation therapy

for patients newly diagnosed with glioblastoma multiforme. Adverse effects: Relatively minor, but may include constipation,

nausea and vomiting, fatigue, and headache..

Temozolomide

Classification = alkylating agent Rapid conversion at physiologic pH to MTIC, CSF concentration

is 30% of serum MTIC cytotoxicity due to methylation of DNA at the O6 position

of guanine Antitumor activity is schedule dependent Cytotoxicity influenced by levels of MGMT Levels not infuenced by cytochrome p450 Renal and hepatic clearance minor

Treatment Schedule

*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase

Significant Improvement in Survival

Gefitinib

Potent and selective inhibitor of EGFR tyrosine kinase EGFR expression and over-expression in GBM other

brain cancers Over-expression correlated with poor prognosis in

many cancers Once-daily, oral dosing Lipophilic compound but CNS levels are low

THANK YOU

For any queries, please contact me at: shivanichauhan232@gmail.com