TEMOZOLOMIDE

DR SAILENDRADEPT. OF RADIOTHERAPYMAULANA AZAD NEDICAL COLLEGE

ADJUVANT TREATMENT RECOMMENDATION FOR GBM

• Irradiate the tumor (everything within) 3 cm margin around tumor i.e (GTV + 3cm margin), keeping in mind the CNS organs at risk .

• Treatment in Conventional schedule-60 Gy/ 30# , 2 Gy daily over 6 wks

• Radiation therapy along with TMZ is recommended in newly diagnosed GBM .

TEMOZOLOMIDE• Alkylating agent• Temodar (U.S), Temodal (international).• Scheringe

• MTIC(3-methyl-triazene-1yl-imadazole-4-carboxamide)

MECHANISM OF ACTION• Imidazotetrazine analog that is structurally and

functionally similar to dacarbazine.• Cell cycle–nonspecific agent.• Metabolic activation to the reactive compound

MTIC is required for antitumor activity.• precise mechanism of cytotoxicity is unclear• methylates guanine residues in DNA and inhibits

DNA, RNA, and protein synthesis.

• Stable at acidic ph(<5) and labile at ph>7.• Prodrug,rapid hydrolysis at physiological pH

active metabolite MTIC(3-methyl-triazene-1yl-imadazole-4-carboxamide).

• MTIC: active metabolite of dacarbazine.

MECHANISM OF RESISTANCE

• Increased activity of DNA repair enzymes such as O6-methylguanineDNAmethyletransferase.

• 40%–50% of the parent drug is excreted in urine within 6 hours of administration, and tubular secretion is the predominant mechanism of renal excretion.

• Widely distributed in body tissues.• Rapidly and completely absorbed with an oral

bioavailability approaching 100%.• Maximum plasma concentrations are reached

within 1 hour

DOSAGE• Temozolomide is given at 75 mg/m2 PO daily for 42

days along with radiotherapy (60 Gy in 30 fractions) for newly diagnosed GBM.

• MAINTENANCE PHASE-• started 4 weeks after completion of RT• In cycle 1 at 150 mg/m2 PO daily for five days

followed by 23 days gap.• Dose of temozolomide may be escalated to 200

mg/m2 if tolerated.• Total 6 cycles to be given.

DRUG INTERACTION• Drug interactions: valporic acid -

clearance by 5%• No influence:Dexamethason Phenytoin Carbamazapine H1/H2 receptor blockers Phenobarbitone

TOXICITY• Myelosuppression. Dose-limiting toxicity.

Leukopenia and thrombocytopenia are commonly observed.

• Photosensitivity.• Teratogenic.• Nausea and vomiting.

-Aggressive antiemetic therapy strongly recommended.

• Headache and fatigue.

RT(N=286) RT/TMZ(N=287) P-valuesMedian age(range)yr

56.6(23.1-70.8) 55.7(19-70.5) NS

Tumor resection 70% 68% NSWHO PS: 0/ 1/ 2(%)

39/ 49/ 12 39/ 48/ 13 NS

Steroids at baseline

75% 67% P=0.041

PFS( 95% CI ) 5 mth(4.2 - 5.5) 7.2 mth (5.8 - 8.3)

P<.0001

Median survival (95% CI )

12mth (11.2-13.2)

15 mth(13.6-16.8)

P<.0001

2yr survival(95% CI )

8%(4-12%) 26%(20-32%) P<.0001

TEMOZOLOMIDE:PHASE III EORTC/NCIC TRIAL RESULTS

537 patients,85 centers Stupp et.al (June 2004)

PFS BENEFIT

OS BENEFIT

On 2005 trial demonstrated that knowledge of the O 6 -methylguanine-DNA methyl transferase (MGMT), ENZYME FOR DNA

REPAIR

Conclusion :This trial showed that patients with methylated (silenced) MGMT promoter sequences had

a median survival of 21.7months versus 15.3 months for those who were not MGMT silenced, in the radiotherapy alone

MGMT is a “suicide enzyme” removes methyl groups from the O6 position of guanine, thus avoiding apoptosis & decrease the activity of TMZ .

Epigenetic silencing of the MGMT gene through promoter methylation leads to increased overall survival and better response to TMZ

NEWER AGENTS

• CARMUSTINE WAFERS• ERLOTINIB• GEFITINIB

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