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Temozolomide As A Radiosensitizer Clinical Experience At Kmio

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  • 1. TEMOZOLOMIDE AS A RADIOSENSITIZER -CLINICAL EXPERIENCE AT KMIO. Dr. B. Krishnamurthy Reddy, Dr.V.Lokesh, Dr.Vijaybhaskar Prof & Head Radiation Oncology Kidwai Memorial Institute of Oncology BANGALORE.
  • 2. BRAIN TUMORS AT KMIO 1998
    • Total: 213 out of 7062 new patients ( 3%)
    • Male:131, Female: 52 & Children:30
    • Grade III /IV Astrocytomas 50% : 90,
    • Astrocytoma unclassified:29
    • Brainstem Glioma:13,Ependymoma:5
    • Oligodendroglioma:9,
    • Medulloblastoma:10, Craniopharyngioma:4, Brain Mets:23,Others=30
    • (Pitutary , Pinealoblastoma, Lymphoma, cerebella Astrocytoma & Others).
  • 3. TREATMENT OPTIONS & OUT COME AT K.M.I.O
    • SURGERY : Biopsy/Subtotal/Near .total Excision.
    • RADIOTHERAPY: GTV with 2 to 3 cms clearance 60 Gy @ CF.
    • CHEMOTHERAPY +- CT : Nitrosoureas.
    • Results : Med- Survival: GBM<1 year (8 mo) AA: 2years
  • 4. FACTORS INFLUENCING FAVOURABLE OUTCOME IN GLIOMAS
        • Younger Age; Low Grade; Good K.P.S (>80);
        • Oligodendroglioma with Ch. 1p and 19 q loss.
        • Adequate surgery & P.O.R.T
        • Temozolomide as Concurrent & Adjuvant (>2001)
  • 5. CONCOMITANT & ADJUVANT TEMOZOLAMIDE WITH RADIOTHERAPY FOR NEWLY DIAGNOSED Gr.III / Gr.IV GLIOMAS ,
    • Investigator initiated study
    • (2002 – 2006)
    • Department of Radiation Oncology; K.M.I.O, Bangalore.
  • 6. RATIONALE FOR THE STUDY
    • Proved efficacy : in vitro: additive and synergistic activity.
    • 1. TMZ+Concurrent RT :
    • Demonstrated additive cytotoxicity against W 373 MG GBM cell Line (with low AGT (alkylguanine, alkyl transferase enzyme) expression.)
    • (Wedge SR, Anticancer Drugs 8: 92-97, 1997)
    • 2. TMZ shown to induce G2-M arrest in gliomacells,
    • thus synchronizing the cell cycle in a radiosensitive phase.
    • (Hirose Y: Cancer Res: 61:1951-1963, 2001)
  • 7. RATIONALE FOR THE STUDY contd..
    • Proved efficacy : in vivo: additive and synergistic activity .
    • Phase II Trial in rec. GBM:
    • Objective R.R. 8%, overall RR: 53%, 6 months . PFS=18% & O.S=46%.
    • TMZ was well tolerated with Grade ¾ Neutropenia & Thrmbocytopenia < 10
    • (Bradey M: Ann oncology. 12:259-2366, 2001)
    • 2. Pre-RT TMZ in newly GBM: RR=43% (CR-9%) (Friedman et al)
    • Report of OS at 1 yr : 58%, at 2 yr:
    • 31% in newly GBM with concurrent & adj.TMZ
    • (R.Stupp et al in J.of cli.oncol. 20: 1375-1328, 2002)
    • 4. Oral Administration:
    • 100% of bioavailability, readily crosses the BBB.with plasma-CSF Ratio of 30%.
  • 8. OBJECTIVES:
    • To evaluate the efficacy & safety
    • To Improve survival
  • 9. ELIGIBILITY:
    • Newly diagnosed HGG (Gr III , IV)
    • Adequate bone marrow, hepatic, renal function
    • No other severe underlying disease
    • Written informed consent
  • 10. TRIAL DESIGN :
    • Page: 11 9
  • 11. Patients Charecteristics treated with TMZ with RT
    • Patients Treated : 14
    • Female : 8
    • Male : 6
    • Mean Age : 40 (18-65)
    • Mean KPS : 70 (60-90)
    • GBM : 4
    • AA : 5
    • AO : 5
  • 12.
    • Surgery:
    • Biopsy : 2
    • Craniotomy & Decompression : 11
    • Near total excision : 1
    • TMZ:
    • Only Concurrent : 6
    • Concurrent & Adjuvant : 8
    Patients Charecteristics treated with TMZ with RT (contn..)
  • 13.
    • Evaluation of Response:
    • Only Clinical : 6
    • Clinical & MRI : 1
    • Clinical & CT Scan : 7
    Patients Charecteristics treated with TMZ with RT (contn..)
  • 14. Toxicity:
    • Hematological :
      • Concurrent : nil
      • Adjuvant : Leukopenia - 2 (14%)
    • Non Hematological: nil
  • 15. Response to Treatment
    • CR : 6
    • PR : 2
    • SD : 1
    • PD & dead : 5 (3 – AA, 2- GBM)
  • 16. CASE NO: 2 (OS: 26 mo, CR : 8mo )
  • 17. CASE NO: 4 (OS: 26 mo, CR : 4mo )
  • 18. CASE NO: 11 (OS: 9 mo, near CR : 3mo )
  • 19. SURVIVAL DATA Follow up - 100% Mean follow up - 15 ( 7 - 26mo) Alive - 9 Mean PFS - 13.5 mo Mean OS - 15.29 mo 1 Year Survival - 75% 2 Years O. Survival - 53% 2 Years PFS - 64%
  • 20. os
  • 21. PFS
  • 22. SURVIVAL VS INFLUENCING FACTORS
    • Variable n mean mo 1yr. % 2Yr. %
    • n 14 13.5 75% 53%
    • ANA.A 10 16.90 * *
    • GBM 4 11.25
    • CCT & Ad. 8 14.88 * *
    • Only CCT 6 15.83
    • (* Case members limited)
  • 23. CONCLUSION
    • TMZ in concurrent & Adjuvant setting with RT is safe & well tolerated
    • Estimated mean survival is 13.5 mo
    • 2 year survival is 53%
  • 24. Thank You