Optimizing Chemotherapy For Malignant Glioma

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



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: [email protected] or Roger Stupp: [email protected]

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


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


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

Optimizing Chemotherapy For Malignant Glioma

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