Temozolomide- first-line treatment for glioblastoma multiforme and second-line treatment for astrocytoma

1. TEMOZOLOMIDE
-Dr. Sanketh Kotne
M.D(Radiation Oncology) D.M. (Medical Oncology)

2. ● Alkylating agent
● Non-cell cycle specific- most active in the resting phase
of the cell
● Oral chemotherapy drug

3. Mechanism of Action
● a prodrug; imidazotetrazine derivative of the alkylating
agent dacarbazine
● Converted to the active alkylating metabolite MTIC
[(methyl-triazene-1-yl)-imidazole-4-carboxamide]
− Spontaneous
− Nonenzymatic
− occurs under physiologic conditions in all tissues to
which it distributes
● Alkylation (methylation) of DNA at the O6, N7 guanine
positions→ DNA double strand breaks/apoptosis

6. INDICATIONS
First licensed in 1999, initially as a second line treatment for
GBM
● Nitrosourea- and procarbazine-refractory anaplastic
astrocytoma
● Newly diagnosed glioblastoma multiforme
Off-label uses:
● Melanoma, advanced or metastatic
● Neuroendocrine tumors, advanced
● Primary CNS lymphoma, refractory
● Brain metastasis of triple-negative breast cancer

7. Stupp et al

8. ADMINISTRATION
● Oral
● Absorption: Oral; Rapid and complete
● IV temozolomide, infused over 90 minutes, is bioequivalent to
an oral dose
● No renal/hepatic dose adjustments
● Take on an empty stomach
● Do not open, crush, or chew capsules
● Antiemetics are recommended to prevent nausea and vomiting

9. DOSING
Concomitant phase:
− 75 mg/m2 once daily for 42 days with focal radiotherapy
Maintenance phase (consists of 6 treatment cycles):
● Begin 4 weeks after concomitant phase completion
− Cycle 1: 150 mg/m2 once daily for 5 days of a 28-day cycle
− Cycles 2-6: May increase to 200 mg/m2 once daily for 5 days

10. ADVERSE REACTIONS
● Lymphocytopenia
● Thrombocytopenia
● Neutropenia
● Leukopenia
● Fatigue
● Headache
● Dizziness
● Ataxia
● Viral infection
● Hypersensitivity reaction

11. MONITORING PARAMETERS
CBC with differential and platelets
● Prior to each cycle;
● Weekly during glioma concomitant phase treatment;
● At or within 48 hours of day 22 and weekly until ANC
>1,500/mm3 and platelets >100,000/mm3 for glioma
maintenance and astrocytoma treatment.
Monitor LFTs at baseline, halfway through the first cycle, prior to
each subsequent cycle, and at ~2 to 4 weeks after the last dose.

12. Markers for GLIOMAS
● MGMT (methyl guanine methyl transferase)
● 1p19q
● IDH(isocitrate dehydrogenase)

13. ● MGMT methylation status ?
*Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N
Engl J Med 2005; 352:997.
Hegi ME, Liu L, Herman JG, et al. Correlation of O6methylguanine methyltransferase (MGMT) promoter
methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin
Oncol 2008; 26:4189

15. ● Unfortunately only 1/3rd of the patients have MGMT
methylation
● Basis of this mechanism?

16. DNA methylation : Inactivates a Promoter region
If no promoter region- No gene [MGMT]
If no MGMT- Doesn't stop TMZ
Chemotherapy

17. ● Methylated MGMT- Better prognosis
Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma.
N Engl J Med 2005; 352:997.

18. Relation with IDH
● IDH- part of Citric acid cycle in glucose metabolism
●
2-HG:
2-hydroxyglutarate
Oncometabolite

19. ● Most frequent mutations in diffuse gliomas
− diffuse astrocytoma
− anaplastic astrocytoma
− oligodendroglioma
− anaplastic oligodendroglioma
− oligoastrocytoma
− anaplastic oligoastrocytoma
− secondary glioblastoma
● wild-type IDH1 gene -Median OS: 1yr
● IDH1 mutant tumors Median OS: 2yrs

20. ● IDH1 mutation was associated with
significantly improved median survival
− Grade II gliomas (151 versus 60 months)
− Grade III gliomas (81 versus 19 months)
− Glioblastomas (27 versus 14 months)
Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognosti
c biomarker in gliomas. J Clin Oncol 2009; 27:4150.
*Mechanism: MGMT promoter methylation is due to an IDH mutation -
induced CpG island hypermethylation phenotype
Improved outcome associated with MGMT methylation is related to
the improved outcome of IDH mutated tumors

21. Grade III glioma:
● Improved outcome associated with MGMT methylation is related
to the improved outcome of IDH mutated tumors.
NOA-4 study :
● MGMT promoter methylation-
independent prognostic variable in IDH1mutant tumors only;
● In IDH1 wildtype tumors, MGMT promoter methylation
was predictive of a response to chemotherapy but not prognostic

22. 1p19q co-deletion
● Major prognostic & predictive factor for improved survival and
responsiveness to therapy in oligodendroglial tumors.
− Anaplastic oligodendroglioma(70-80%)
− Anaplastic oligoastrocytoma(50%)

23. combined loss of the short arm chromosome 1 (“1p”) and the long arm of
chromosome 19 (“19q”)

24. ● IDH1 positive + 1p19q codeletion : better prognosis
(oligodendroglioma / oligoastrocytoma)
● IDH1 positive + no 1p19q codeletion = shorter overall survival
(astrocytoma)

25. ● All gliomas with 1p19q codeletion are IDH mutated
● A strong predictor of response to the procarbazine,
lomustine and vincristine (PCV) regimen [Cairncross et
al.,RTOG]
● TMZ vs PCV :
− Longer TTP compared to TMZ (Lassman 2011)

26. THANK YOU