Temozolomide As A Radiosensitizer Clinical Experience At Kmio

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Temozolomide As A Radiosensitizer Clinical Experience At Kmio

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

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