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Optimizing Chemotherapy For Malignant Glioma
 

Optimizing Chemotherapy For Malignant Glioma

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Optimizing Chemotherapy For Malignant Glioma Optimizing Chemotherapy For Malignant Glioma Presentation Transcript

  • 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
  • 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