TEMOZOLOMIDE AS A TEMOZOLOMIDE AS A RADIOSENSITIZERRADIOSENSITIZER

-CLINICAL EXPERIENCE AT KMIO.-CLINICAL EXPERIENCE AT KMIO.

Dr. B. Krishnamurthy Reddy, Dr. B. Krishnamurthy Reddy, Dr.V.Lokesh, Dr.VijaybhaskarDr.V.Lokesh, Dr.Vijaybhaskar

Prof & Head Radiation OncologyProf & Head Radiation Oncology

Kidwai Memorial Institute of OncologyKidwai Memorial Institute of OncologyBANGALORE.BANGALORE.

BRAIN TUMORS AT KMIO BRAIN TUMORS AT KMIO 19981998

Total: 213 out of 7062 new patients ( 3%)Total: 213 out of 7062 new patients ( 3%)

Male:131, Female: 52 & Children:30Male:131, Female: 52 & Children:30

Grade III /IV Astrocytomas 50% : 90, Grade III /IV Astrocytomas 50% : 90, Astrocytoma unclassified:29Astrocytoma unclassified:29

Brainstem Glioma:13,Ependymoma:5Brainstem Glioma:13,Ependymoma:5Oligodendroglioma:9,Oligodendroglioma:9,Medulloblastoma:10, Craniopharyngioma:4, Brain Medulloblastoma:10, Craniopharyngioma:4, Brain Mets:23,Others=30Mets:23,Others=30(Pitutary , Pinealoblastoma, Lymphoma, cerebella (Pitutary , Pinealoblastoma, Lymphoma, cerebella Astrocytoma & Others).Astrocytoma & Others).

TREATMENT OPTIONS & OUT COME AT K.M.I.OTREATMENT OPTIONS & OUT COME AT K.M.I.O

SURGERYSURGERY : : Biopsy/Subtotal/Near .total Biopsy/Subtotal/Near .total Excision.Excision.

RADIOTHERAPY: RADIOTHERAPY: GTV with 2 to 3 cms GTV with 2 to 3 cms clearance 60 Gy @ CF.clearance 60 Gy @ CF.

CHEMOTHERAPY +- CTCHEMOTHERAPY +- CT : : Nitrosoureas.Nitrosoureas.

Results :Results : Med- Survival: GBM<1 year (8 mo) Med- Survival: GBM<1 year (8 mo) AA: 2yearsAA: 2years

FACTORS INFLUENCING FAVOURABLE FACTORS INFLUENCING FAVOURABLE OUTCOME IN GLIOMASOUTCOME IN GLIOMAS

Younger Age; Low Grade; Good K.P.S (>80); Younger Age; Low Grade; Good K.P.S (>80);

Oligodendroglioma with Ch. 1p and 19 q loss.Oligodendroglioma with Ch. 1p and 19 q loss.

Adequate surgery & P.O.R.T Adequate surgery & P.O.R.T

Temozolomide as Concurrent & Adjuvant (>2001)Temozolomide as Concurrent & Adjuvant (>2001)

CONCOMITANT & ADJUVANT TEMOZOLAMIDE CONCOMITANT & ADJUVANT TEMOZOLAMIDE

WITH RADIOTHERAPY WITH RADIOTHERAPY FOR NEWLY DIAGNOSED Gr.III / Gr.IV FOR NEWLY DIAGNOSED Gr.III / Gr.IV

GLIOMASGLIOMAS,,

Investigator initiated studyInvestigator initiated study (2002 – 2006)(2002 – 2006)

Department of Radiation Oncology;Department of Radiation Oncology; K.M.I.O, Bangalore. K.M.I.O, Bangalore.

RATIONALE FOR THE STUDYRATIONALE FOR THE STUDYProved efficacyProved efficacy: in vitro: : in vitro: additive and synergisticadditive and synergistic activity. activity.

1. TMZ+Concurrent RT1. TMZ+Concurrent RT:: Demonstrated Demonstrated additiveadditive cytotoxicity against W 373 MG GBM cell Line cytotoxicity against W 373 MG GBM cell Line

(with low AGT (alkylguanine, alkyl transferase enzyme) expression.)(with low AGT (alkylguanine, alkyl transferase enzyme) expression.) (Wedge SR, Anticancer Drugs 8: 92-97, 1997)(Wedge SR, Anticancer Drugs 8: 92-97, 1997)

2. TMZ shown to induce G2-M arrest in gliomacells,2. TMZ shown to induce G2-M arrest in gliomacells, thus synchronizing the cell cycle in a thus synchronizing the cell cycle in a radiosensitiveradiosensitive phase. phase. (Hirose Y: Cancer Res: 61:1951-1963, 2001)(Hirose Y: Cancer Res: 61:1951-1963, 2001)

RATIONALE FOR THE STUDY contd..RATIONALE FOR THE STUDY contd..Proved efficacyProved efficacy: in vivo: : in vivo: additive and synergistic activityadditive and synergistic activity. .

1.1. Phase II Trial in rec. GBM:Phase II Trial in rec. GBM: Objective R.R. 8%, overall RR: 53%, 6 months . PFS=18% & O.S=46%.Objective R.R. 8%, overall RR: 53%, 6 months . PFS=18% & O.S=46%.TMZ was well tolerated with Grade ¾ Neutropenia & Thrmbocytopenia < 10TMZ was well tolerated with Grade ¾ Neutropenia & Thrmbocytopenia < 10

(Bradey M: Ann oncology. 12:259-2366, 2001)(Bradey M: Ann oncology. 12:259-2366, 2001)

2. 2. Pre-RT TMZ in newly GBM:Pre-RT TMZ in newly GBM: RR=43% (CR-9%) RR=43% (CR-9%) (Friedman (Friedman et al)et al)

3.3. Report of OS at 1 yr :Report of OS at 1 yr : 58%, at 2 yr: 58%, at 2 yr: 31% in newly GBM with concurrent & adj.TMZ31% in newly GBM with concurrent & adj.TMZ

(R.Stupp et al in J.of cli.oncol. 20: 1375-1328, 2002)(R.Stupp et al in J.of cli.oncol. 20: 1375-1328, 2002)

4. 4. Oral Administration:Oral Administration: 100% of bioavailability, readily crosses the BBB.with plasma-CSF Ratio of 30%.100% of bioavailability, readily crosses the BBB.with plasma-CSF Ratio of 30%.

OBJECTIVES:OBJECTIVES:

To evaluate the efficacy & safetyTo evaluate the efficacy & safety

To Improve survivalTo Improve survival

ELIGIBILITY:ELIGIBILITY:

Newly diagnosed HGG (Gr III , IV)Newly diagnosed HGG (Gr III , IV)

Adequate bone marrow, hepatic, renal Adequate bone marrow, hepatic, renal functionfunction

No other severe underlying diseaseNo other severe underlying disease

Written informed consentWritten informed consent

TRIAL DESIGNTRIAL DESIGN::

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Patients Charecteristics treated Patients Charecteristics treated with TMZ with RTwith TMZ with RT

Patients TreatedPatients Treated :: 1414FemaleFemale :: 88MaleMale :: 66Mean AgeMean Age :: 40 (18-65)40 (18-65)Mean KPSMean KPS :: 70 (60-90)70 (60-90)GBMGBM :: 4 4 AAAA :: 55AOAO :: 55

Surgery:Surgery:Biopsy Biopsy :: 22Craniotomy & DecompressionCraniotomy & Decompression : : 1111Near total excisionNear total excision :: 11

TMZ:TMZ:Only ConcurrentOnly Concurrent :: 66Concurrent & AdjuvantConcurrent & Adjuvant :: 88

Patients Charecteristics treated Patients Charecteristics treated with TMZ with RT (contn..)with TMZ with RT (contn..)

Evaluation of Response:Evaluation of Response:

Only ClinicalOnly Clinical :: 66

Clinical & MRIClinical & MRI :: 11

Clinical & CT ScanClinical & CT Scan :: 77

Patients Charecteristics treated Patients Charecteristics treated with TMZ with RT (contn..)with TMZ with RT (contn..)

Toxicity: Toxicity:

Hematological :Hematological :– Concurrent Concurrent : : nilnil– Adjuvant Adjuvant :: Leukopenia - 2Leukopenia - 2 (14%)(14%)

Non Hematological: nilNon Hematological: nil

Response to TreatmentResponse to Treatment

CRCR :: 66

PRPR :: 22

SDSD :: 11

PD & deadPD & dead :: 5 (3 – AA, 2- 5 (3 – AA, 2- GBM)GBM)

CASE NO: 2 (OS: 26 mo, CR : 8mo )

CASE NO: 4 (OS: 26 mo, CR : 4mo )

CASE NO: 11 (OS: 9 mo, near CR : 3mo )

SURVIVAL DATASURVIVAL DATA

Follow up Follow up - - 100% 100% Mean follow up Mean follow up - - 15 ( 7 - 26mo)15 ( 7 - 26mo)AliveAlive - - 99Mean PFSMean PFS - - 13.5 mo13.5 moMean OSMean OS -- 15.29 mo15.29 mo1 Year Survival1 Year Survival -- 75%75%2 Years O. Survival2 Years O. Survival -- 53%53%2 Years PFS2 Years PFS -- 64%64%

osos

PFSPFS

SURVIVAL SURVIVAL VSVS INFLUENCING FACTORS INFLUENCING FACTORS

VariableVariable n n mean momean mo 1yr. % 1yr. % 2Yr. %2Yr. %

nn 14 14 13.513.5 75% 75% 53% 53%

ANA.AANA.A 10 10 16.9016.90 * * * *

GBMGBM 4 4 11.2511.25

CCT & Ad. 8CCT & Ad. 8 14.8814.88 * * * *

Only CCTOnly CCT 6 6 15.8315.83

(* Case members limited)(* Case members limited)

CONCLUSIONCONCLUSION

TMZ in concurrent & Adjuvant setting with TMZ in concurrent & Adjuvant setting with RT is safe & well toleratedRT is safe & well tolerated

Estimated mean survival is 13.5 moEstimated mean survival is 13.5 mo

2 year survival is 53%2 year survival is 53%