Post on 23-Jan-2015
description
Optimizing Chemotherapy for Malignant Glioma
State of the Art & Future Directions
Roger Stupp, MDMultidisciplinary Oncology Center
University Hospital (CHUV)Lausanne / Switzerland
Lancet 359:1011-1018, 2002
Meta-analysis: Survival
12-mo surv: 40% 46%24-mo surv: 15% 20%median: + 2 mo
Wedge SR, et al. Anticancer Drugs. 1997;8:92-97.* In-vitro studies of U373MGglioblastoma cell line
Radiation (Gray)
35
30
25
20
15
10
5
00 1 2
Inh
ibit
ion
of
Ce
ll G
row
th (
%) RT only
RT + 5 ตM TMZ
RT + 10 ตM TMZ
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)
PreTx Day 15 Day 22
0
5
10
15
20Pretreatment vs Day 22 (p < 0.001)
Pretreatment vs Day 15 (p < 0.001)
AG
AT
Act
ivit
y (f
mo
l/g
DN
A)
Mean ฑ SD: 5.8 ฑ 3.5
Mean ฑ SD: 1.8 ฑ 1.4
Mean ฑ SD: 1.5 ฑ 1.4
Tolcher et al. Br J Cancer 88:1004-1011,2003
(N = 14 paired specimens)
AGAT (= MGMT) Activity:TMZ 21d continuous
TMZ 75mg/m2 qd x 6-7 wks
TMZ 200 mg/m2 qd x 5 dayrepeat every 28 days
x 6 cycles
wksFocal Radiotherapy (30 x 2 Gy, 60 Gy)Tumor volume with 2-3 cm margin
TMZ & RT: Treatment Scheme
TMZ & RT: Promising Survival
Median: 14.3 mo(95% c.i. 10.4-18.3)
1 yr: 56% (44-68%)
2 yr: 28% (17-39%)
N = 64 (January 2003)
Median follow-up: 39 moMininum า 28 moAlive 10 pts
months
Surv
ival
Stupp R et al. J Clin Oncol. 2002;20:1375-82Stupp R & Hegi ME. ASCO Education Book, 2003
Phase III Trial of Concomitant and Adjuvant Temozolomide and
Radiotherapy for Newly Diagnosed Glioblastoma
MultiformeEORTC 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 MirimanoffOn 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
Temozolomide 75 mg/m2 po qd for 6 weeks,then 150–200 mg/m2 po qd d1–5 every 28 days for 6 cycles
Focal RT daily — 30 x 200 cGyTotal dose 60 Gy
Concomitant TMZ/RT*
Adjuvant TMZ
Weeks6 10 14 18 22 26 30
RT Alone
R
Treatment Schema
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
RT Alonen=286
TMZ/RTn=287
Median age, yr 57(23–71)
56(19–70)
M/F (%) 61/39 64/36
PS 0–1 vs 2 (%) 88/12 87/13
Baseline Steroids (%)
75 67
Debulking surgery 84 83
Biopsy only 16 17
Patient Characteristics
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
RT Alonen=286
%
TMZ/RTn=287
%
Anemia 0 <1
Leukopenia 0 3
Neutropenia 0 4
Febrile neutropenia 0 1
Thrombocytopenia 0 3
Fatigue/Constitutional Sx
6 9
Rash/Dermatologic 1 1
Nausea/Vomiting 1 <1
Infection 2 3
Visual 1 1
Hem
ato
. to
x.
Non-h
em
. to
x.
0102030405060708090
100
1 2 3 4 5 6
Cycle
% pt
ProgressionToxicityOtherCompleted
Adjuvant TMZ Treatment
Deliveryn=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 36 420
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :
281 286 104 26 11 4 0 0260 287 154 77 51 24 8 1
RT TMZ/RTMedian PFS, mo: 5.0 6.91-yr PFS: 9% 27%2-yr PFS: 2% 11%HR [95% C.I.]: 0.54 [0.45-0.64]
p <0.0001
TMZ/RTRT
TMZ/RTRT
%
Stupp et al. N Engl J Med 2005, 352:987-996
Overall Survival
months
0 6 12 18 24 30 36 420
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :
261 286 240 144 59 23 2 0219 287 246 174 109 57 27 4
RT TMZ/RT
Median OS, mo: 12.1 14.62-yr survival: 10% 26%HR [95% C.I.]: 0.63 [0.52-0.75]
p <0.0001
RTTMZ/RT
TMZ/RT
RT
%
Stupp et al. N Engl J Med 2005, 352:987-996
Subset AnalysisOverall Survival
ITT Population (286/287)
Age < 50 (81/90) ≥ 50 (205/197)
Biopsy Only (46/47)Resected (240/240)
WHO PS = 0 (112/116) PS = 1 (140/135) PS = 2 (34/36)
Mini-mental status ≥ 29 (148/149) ≤ 28 (126/128)
Baseline steroids (215/193)No Baseline steroids (70/94)
Males (175/185)Females (110/102)
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)
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
NN
NN
NN
NN NHNH22
OO
dRdR
O6-methylguanine
CHCH33
MGMT Gene
• located on CHR 10q26
• encodes DNA repair enzyme
• removes methyl-groups from O6alkylguanine
• linked with resistance to alkylating agent therapy
•TMZ, methylating agent
MGMT
NH2
NH
CH2 CH
CO
COOH
HS
repair
Guanine
N
N
N NH2
O
dR
NH
•irreversible inactivationinactivation•degradation
NH2
NH
CH CH
CO
COOH
S2
CHCH33
06-Methylguanine-DNA Methyltransferase (MGMT)
MGMT GENE
expressionexpression
Promoter region expressionexpression
Normal
Tumor
Tumor
•No repair protein•No repair of TMZ treatment induced DNA damage
•Response to tumor treatment•Improved survival of glioblastoma patient
methylatednononono« turned off »
MGMT repair gene silencing by gene promoter
methylation
0 5 10 15 20 25 30 35 400
10
20
30
40
50
60
70
80
90
100
months
Ove
rall
Su
rviv
al
UnmethylatedN = 114 (55%)
Methylated, N = 92 (45%)
N=206
Unmeth Meth
Median OS, mo: 12.218.2HR [95% CI]: 0.45 [0.32-0.61]Logrank test: p <0.0001
Risk of death reduced by 55%
MGMT Promoter Methylation is Prognostic
Hegi et al. N Engl J Med, 352: 997-1003, 2005
months
0 4 8 12 16 20 24 28 32 36 400
10
20
30
40
50
60
70
80
90
100
Ov
era
ll S
urv
iva
l
TMZTMZ/ RT
RT
Unmethylated MGMT RT TMZ/RT
Median OS, mo: 11.8 12.72-yr survival: 1.9% 13.8%
Logrank : p = 0.062
Methylated MGMT
0 5 10 15 20 25 30 35 400
10
20
30
40
50
60
70
80
90
100
TMZTMZ/ RT
RT
months
RT TMZ/RT
Median OS mo: 15.3 21.72-yr surviva,l 22.7% 46.0%
Logrank : p = 0.0074
MGMT is Predictive for Benefit from TMZ Treatment
Hegi et al. N Engl J Med 2005, 352:997-1003
2217Palliative Care only
54Repeat RT
2323Surgery
2565Temozolomide
5872Any Additional Chemotherapy
TMZ/RTn=287
%
RT Alonen=286
%
At the discretion of treating physician
Treatment after Progression
months0 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 0 053 60 44 18 8 8 8 7 5 3 145 46 33 15 7 3 2 1 0 0 040 46 35 28 18 14 10 6 3 1 0
Unmeth, RT aloneUnmeth, TMZ/ RTMeth, RT aloneMeth, TMZ/ RT
Overall Wald test: p <0.0001 (df=3)
Pro
gre
ss
ion
Fre
e S
urv
iva
l
Meth, TMZTMZ/ RT
Meth, RT
Unmeth, TMZTMZ/ RTUnmethRT
PFS: MGMT Methylation Status: a predictive factor for TMZ benefit
Hegi et al. N Engl J Med 2005, 352:997-1003
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 methylationTi
ssue
For additional information contact: RTOG: www.rtog.org or EORTC: www.eortc.be; or the study chairs: Mark Gilbert: mrgilbert@mdanderson.org or Roger Stupp: Roger.Stupp@chuv.ch
RTOG0525/EORTC Intergroup
Phase III Study
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 survivalP=0.002
Overall survivalP=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 LOH
No LOH
1p/19q LOH
No 1p LOH
PCV +PCV -
PCV +PCV -
Overall survival bygenetic marker
Genetic markerand treatment
van den Bent et al. J Clin Oncol 24:2715-2722, 2006
R
Radiotherapy (33x1.8 Gy) Adj. PCV (6 cycles)
N=185
N=183
Radiation TherapyOncology Group
0
25
50
75
100
0 1 2 3 4 5 6 7Years
% A
live
N MST
PCV+RT 148 4.9 yr.
RT Alone 143 4.7 yr.
HR = 0.94, p = 0.42
Overall Survival by Treatment ArmRadiation TherapyOncology Group
0
25
50
75
100
0 1 2 3 4 5 6 7
Years
% A
live
w/o
Pro
gres
sion
N MST
PCV+RT 148 2.5 yr.
RT Alone 143 1.9 yr.
HR = 0.73, p = 0.018
Progression-free Survivalby Treatment Arm
RTOG 94-02: Chemo for oligos
Cairncross et al. J Clin Oncol 24:2707-2714, 2006
R
Radiotherapy (33x1.8 Gy) Adj. PCV (6 cycles)
N=185
N=183
Cairncross et al. J Clin Oncol 24:2707-2714, 2006
Radiation TherapyOncology Group Survival by 1p and 19q Status
Years
% A
live
N MST
1p- and 19q- 92 -
One/Neither 109 2.8 yr
HR = 0.31, p < 0.001
0
25
50
75
100
0 1 2 3 4 5 6 7
Radiation TherapyOncology Group
0
25
50
75
100
0 1 2 3 4 5 6 7
Survival by Treatment Arm: Patients with 1p and 19q Loss
Years
% A
live
n MST
PCV+RT 43 Not Reached
RT Alone 50 6.6 yr.
p = 0.88
RTOG 94-02: Chemo for oligos
TMZ in Oligos
Histology n RR 1-y PFS
Remarks Study
Astrocytoma (2), AOA (14), AOD (23)
39 53% 40% First-line therapy van den Bent et al .
AOA (11), AOD (17), other (4)
32 31% 11% Failed previous PCV after initial response in 31%
van den Bent et al .
AOA (9), AOD (39)
48 44% 25% Failed previous PCV after initial response in 44%
Chinot et al .
Adapted from Stupp et al. Curr Opin Neurol 2005
TMZ in low-grade glioma
Histology n RR 1-y PFS Remarks Study
Astrocytoma (17), OA (2), OD (11)
30 10% (+48% MR) 76% (at 2 y) Primary therapy Brada et al
OA (11), OD (49) 60 17% (+14% MR) 73% Many delayed responses
Hoang-Xuan et al
Astrocytoma (16), OA (5), OD (20), other (5)
46 61% 76% Contrast+ in 70% Quinn et al
Astrocytoma (29), OA (10), OD (4)
43 47% 39% Contras + in 60% Pace et al
Adapted from Stupp et al. Curr Opin Neurol 2005
CHEMOTHERAPY(PCV, TMZ)
RADIOTHERAPY50.4 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
EORTC/NCIC 22033-26033: Phase III Trial in LGG
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