Optimizing Chemotherapy For Malignant Glioma

Optimizing Chemotherapy for Malignant Glioma State of the Art & Future Directions Roger Stupp, MD Multidisciplinary Oncology Center University Hospital (CHUV) Lausanne / Switzerland

Meta-analysis: Survival Lancet 359:1011-1018, 2002 12-mo surv: 40%  46% 24-mo surv: 15%  20% median: + 2 mo

Situation 1998
Synergy between RT and TMZ in vitro
Continuous administration of TMZ feasible, increases drug exposure (Brock, Newlands et al. Cancer Res 58:4363-67, 1998)
Improved outcome of concomitant chemoradiotherapy in other solid tumors (e.g. cervix cancer, head&neck cancer)

TMZ & RT: Treatment Scheme TMZ 75mg/m 2 qd x 6-7 wks TMZ 200 mg/m 2 qd x 5 day repeat every 28 days x 6 cycles wks Focal Radiotherapy (30 x 2 Gy, 60 Gy) Tumor volume with 2-3 cm margin

TMZ & RT: Promising Survival Stupp R et al. J Clin Oncol. 2002;20:1375-82 Stupp R & Hegi ME. ASCO Education Book, 2003

Phase III Trial of Concomitant and Adjuvant Temozolomide and Radiotherapy for Newly Diagnosed Glioblastoma Multiforme EORTC 26981-22981 and NCIC CE.3 Roger Stupp , WP Mason, MJ Van Den Bent, M Weller, B Fisher, MJB Taphoorn, K Belanger, AA Brandes, JG Cairncross, C Marosi, U. Bogdahn, J. Curschmann, RC Janzer, S Ludwin, T Gorlia, A Allgeier, D Lacombe, E Eisenhauer, RO Mirimanoff On behalf of the European Organization for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and National Cancer Institute of Canada Clinical Trials Group

Treatment Schema Temozolomide 75 mg/m 2 po qd for 6 weeks, then 150–200 mg/m 2 po qd d1–5 every 28 days for 6 cycles Focal RT daily — 30 x 200 cGy Total dose 60 Gy Concomitant TMZ/RT* Adjuvant TMZ Weeks 6 10 14 18 22 26 30 RT Alone R 0 *PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.

Patient Eligibility
Newly diagnosed, histologically proven GBM
Age 18–70 years
WHO PS 0-2
≤ 6 weeks since biopsy or resection
No prior chemotherapy or RT
Adequate bone marrow, hepatic and renal function
Written informed consent

Patient Characteristics 17 16 Biopsy only 83 84 Debulking surgery 67 75 Baseline Steroids (%) 87/13 88/12 PS 0–1 vs 2 (%) 64/36 61/39 M/F (%) 56 (19–70) 57 (23–71) Median age, yr TMZ/RT n=287 RT Alone n=286

TMZ / RT Treatment and Surveillance
TMZ 75 mg/m2 daily (7 days per week) from day 1 of RT until last day of RT (max 49 days, theoretical duration 40 days)
TMZ approx. 1 hour before RT
Antiemetic prophylaxis only first days; eg.
Day 1-2: 5HT3 antagonist (e.g. Zofran 4 mg)
Day 3-4: Metoclopramide or Motilium 10 mg
Day 5+: try without any antiemetics
RT daily Monday-Friday, 30 fraction of 2 Gy
Complete blood count weekly
Pneumocystis carinii prophylaxis with either
Pentamidine inhalations every 4 weeks
Trimethoprim/Sulfametoxazole (Bactrim forte) 3 x per wk

During RT ± TMZ: Grade 3/4 Toxicities Hemato. tox. Non-hem. tox. 1 1 Visual 3 2 Infection <1 1 Nausea/Vomiting 1 1 Rash/Dermatologic 9 6 Fatigue/Constitutional Sx 3 0 Thrombocytopenia 1 0 Febrile neutropenia 4 0 Neutropenia 3 0 Leukopenia <1 0 Anemia TMZ/RT n=287 % RT Alone n=286 %

Adjuvant TMZ Treatment Delivery n=287* *22% (n=64) randomized to TMZ/RT did not receive any adjuvant TMZ. Reason for Early Discontinuation: Cycle completed

Progression Free Survival months 0 6 12 18 24 30 36 42 0 10 20 30 40 50 60 70 80 90 100 RT TMZ/RT Median PFS, mo: 5.0 6.9 1-yr PFS: 9% 27% 2-yr PFS: 2% 11% HR [95% C.I.]: 0.54 [0.45-0.64] p <0.0001 TMZ/RT RT TMZ/RT RT % Stupp et al. N Engl J Med 2005, 352:987-996 O N Number of patients at risk : 281 286 104 26 11 4 0 0 260 287 154 77 51 24 8 1

Overall Survival months 0 6 12 18 24 30 36 42 0 10 20 30 40 50 60 70 80 90 100 RT TMZ/RT Median OS, mo: 12.1 14.6 2-yr survival: 10% 26% HR [95% C.I.]: 0.63 [0.52-0.75] p <0.0001 RT TMZ/RT TMZ/RT RT % Stupp et al. N Engl J Med 2005, 352:987-996 O N Number of patients at risk : 261 286 240 144 59 23 2 0 219 287 246 174 109 57 27 4

Subset Analysis Overall Survival 0.0 0.5 1.0 1.5 2.0 Hazard Ratio with 95% C.I. Stupp et al. N Engl J Med 2005, 352:987-996 (appendix) Males (175/185) Females (110/102) Baseline steroids (215/193) No Baseline steroids (70/94) Mini-mental status ≥ 29 (148/149) ≤ 28 (126/128) WHO PS = 0 (112/116) PS = 1 (140/135) PS = 2 (34/36) Biopsy Only (46/47) Resected (240/240) Age < 50 (81/90) ≥ 50 (205/197) ITT Population (286/287)

Implications - Paradigm Change
Chemotherapy improves outcome in patients with malignant glioma, incl. long-term survival (years !)
Prognosis is now comparable or even superior to many of the common solid tumors (e.g. NSCLC)
Concomitant chemoradiotherapy and treatment early in the disease course is of importance.
Identification of patients most likely to benefit from therapy is needed. Clinical criteria alone not helpful.
Molecular Analyses: MGMT

06-Methylguanine-DNA Methyltransferase (MGMT) N N N N O dR
MGMT Gene
located on CHR 10q26
encodes DNA repair enzyme
removes methyl -groups from O 6 alkylguanine
linked with resistance to alkylating agent therapy
TMZ, methylating agent
NH 2 O 6 - methyl guanine CH 3 MGMT NH 2 NH CH 2 CH CO COOH HS repair Guanine N N N NH 2 O dR NH
irreversible inactivation
degradation
NH 2 NH CH CH CO COOH S 2 CH 3

MGMT repair gene silencing by gene promoter methylation MGMT GENE expression Promoter region expression Normal Tumor
Tumor
No repair protein
No repair of TMZ treatment induced DNA damage
Response to tumor treatment
Improved survival of glioblastoma patient
methylated no « turned off »

MGMT Promoter Methylation is Prognostic 0 5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80 90 100 months Overall Survival Unmethylated N = 114 (55%) Methylated, N = 92 (45%) N=206 Unmeth Meth Median OS, mo: 12.2 18.2 HR [95% CI]: 0.45 [0.32-0.61] Logrank test: p <0.0001 Risk of death reduced by 55% Hegi et al. N Engl J Med, 352: 997-1003, 2005

MGMT is Predictive for Benefit from TMZ Treatment Unmethylated MGMT RT TMZ/RT Median OS, mo: 11.8 12.7 2-yr survival: 1.9% 13.8% Logrank : p = 0.062 Logrank : p = 0.0074 Hegi et al. N Engl J Med 2005, 352:997-1003 months 0 4 8 12 16 20 24 28 32 36 40 0 10 20 30 40 50 60 70 80 90 100 Overall Survival TMZ / RT RT Methylated MGMT 0 5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80 90 100 TMZ / RT RT months RT TMZ/RT Median OS mo: 15.3 21.7 2-yr surviva,l 22.7% 46.0%

Treatment after Progression 22 17 Palliative Care only 5 4 Repeat RT 23 23 Surgery 25 65 Temozolomide 58 72 Any Additional Chemotherapy TMZ /RT n=287 % RT Alone n=286 % At the discretion of treating physician

PFS: MGMT Methylation Status: a predictive factor for TMZ benefit months 0 4 8 12 16 20 24 28 32 36 40 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : 54 54 28 9 0 0 0 0 0 0 0 53 60 44 18 8 8 8 7 5 3 1 45 46 33 15 7 3 2 1 0 0 0 40 46 35 28 18 14 10 6 3 1 0 Unmeth, RT alone Unmeth, TMZ/ RT Meth, RT alone Meth, TMZ/ RT Overall Wald test: p <0.0001 (df=3) Progression Free Survival Meth, TMZ / RT Meth, RT Unmeth, TMZ / RT Unmeth RT Hegi et al. N Engl J Med 2005, 352:997-1003

RTOG0525/EORTC Intergroup Phase III Study TMZ daily x 6 wks R Radiotherapy (30 x 2 Gy) Concomitant Phase Adjuvant (maintenance) Phase (6 mo) Dose dense TMZ (100 mg/m2 daily x 21d) Stratify by: MGMT methylation Tissue For additional information contact: RTOG: www.rtog.org or EORTC: www.eortc.be ; or the study chairs: Mark Gilbert: [email_address] or Roger Stupp: [email_address]

1p/19q LOH predicts response to PCV-chemotherapy J. Gregory Cairncross et al JNCI 90:1473-79, 1998

EORTC 26951: RT ± adj. PCV R Radiotherapy (33x1.8 Gy) Adj. PCV (6 cycles) N=185 N=183 Progression-free survival P=0.002 Overall survival P=0.226 van den Bent et al., Proc ASCO 2005 {abstr #1503} van den Bent et al., J Clin Oncol 24:2715-2722, 2006

EORTC 26951: Genetic markers 1p/19q LOH 1p LOH 19q LO H No LOH 1p/19q LOH No 1p LOH PCV + PCV - PCV + PCV - Overall survival by genetic marker Genetic marker and treatment van den Bent et al. J Clin Oncol 24: 2715-2722, 2006

RTOG 94-02: Chemo for oligos R Radiotherapy (33x1.8 Gy) Adj. PCV (6 cycles) N=185 N=183 Cairncross et al. J Clin Oncol 24:2707-2714, 2006

TMZ in Oligos Adapted from Stupp et al. Curr Opin Neurol 2005

TMZ in low-grade glioma Adapted from Stupp et al. Curr Opin Neurol 2005

EORTC/NCIC 22033-26033: Phase III Trial in LGG CHEMOTHERAPY (PCV, TMZ) RADIOTHERAPY 50.4 Gy (28 x1.8 Gy)
Eligibility:
age > 40
tumor > 5 cm
crossing midline/unresectable
neurological symptoms
Stratification:
Age
Resection
Histology (Oligo vs. Astro vs. mixed)
1p loss (yes/no/unknown.)
CHEMOTHERAPY TMZ 75 mg/m2 x 21d / q28d x 12 cy

New Paradigms
Role of chemotherapy is now established
Treat early in the disease course
Concomitant chemoradiotherapy has shown promise in malignant glioma, similar to other solid tumors (e.g. head&neck cancer, cervix cancer, lung cancer)
There is no justification to refuse treatment for malignant glioma patients as prognosis is equivalent and even superior to many other solid tumors.
Temozolomide chemotherapy is a safe and commonly well tolerated treatment.
Identification of patients most likely to benefit from therapy is needed. Clinical criteria alone not helpful
Molecular analyses, availability of fresh tissue should become a mandatory and routine procedure just like the H&E stain

Optimizing Chemotherapy For Malignant Glioma

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