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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
