High grade glioma, standard of care & new advances..

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By Osama Elzaafarany Assistant lecturer of clinical oncology Medical Research Institute-Alexandria University High-grade glioma.. Standard of care & new advancesMarch 2014

description

Aim of this ppt presentation: To understand the standard of care for both GBM and anaplastic glioma. To know what is the new advances and modifications to the standard of care? Contents: Introduction: 2 slides. GBM: Epidemiology: 1 slide. Molecular biology & New trends: 5 slides EORTC/NCIC trial: 10 slides. MGMT: 1 slide. Evidence-based medicine: 6 slides. Avastin in GBM: 2 slides. Novocure (TTF): 2 slides. Gliadel (BCNU) wafers: 1 slide. Anaplastic astrocytoma: 7 slides Take home message.

Transcript of High grade glioma, standard of care & new advances..

Page 1: High grade glioma, standard of care & new advances..

By

Osama Elzaafarany Assistant lecturer of clinical oncology

Medical Research Institute-Alexandria University

High-grade glioma.. Standard of care & new advances…

March 2014

Page 2: High grade glioma, standard of care & new advances..

Contents:

Introduction: 2 slides.

GBM:

Epidemiology: 1 slide.

Molecular biology & New trends: 5 slides

EORTC/NCIC trial: 10 slides.

MGMT: 1 slide.

Evidence-based medicine: 6 slides.

Avastin in GBM: 2 slides.

Novocure (TTF): 2 slides.

Gliadel (BCNU) wafers: 1 slide.

Anaplastic astrocytoma: 7 slides

Take home message.

Aim of this presentation: • To understand the standard of care for both

GBM and anaplastic glioma.

• What is the new advances and modifications

to the standard of care?

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WHO

grade III grade IV

What is high-grade glioma?

GBM

• Anaplastic astrocytoma

• Anaplastic oligodendroglioma

• Anaplastic mixed glioma “oligo-astrocytoma”

Anaplastic

gliomas

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Glioblastoma Multiforme: ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

Most common 1ry malignant brain

tumor in adult.

About 50 % of all gliomas.

1 year survival about 30 %.

Men > females.

Peak incidence: 65-75 ys.

Age median survival.

Malign CNS = 1.4% of all cancers.

1ry CNS tumors ~ 66.000 new

cases/year: (USA, 2012):

=> glioma = 32 %

=> GBM = 16% of 1ry CNS Ts.

~10.000 new cases of GBM/year

Established risk factor:

previous exposure to ionizing radiation:

Pre-natal diagnostic X-rays.

Cranial RTx for ALL: (risk 0.5% at 10ys).

• Hereditary syndromes: 5%

of GBM cases:

• Suspected when you have

multiple brain tumors.

• P53, NF1, Turcot’s.

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Molecular Biology:

GBM characterized by extensive heterogeneity at the cellular and

molecular levels.

Develops either de novo (primary GBM), or as the result of the

malignant progression from a lower-grade glioma (secondary

GBM).

4 molecular sub-types: (classical, mesenchymal, proneural and neural)

The true cellular origin of gliomas, including GBM, is still a

debatable question => Two different hypotheses for the origin:

accumulation of alterations that occur in differentiated mature cells (glial cells).

most recent hypothesis assumes that cancer cells arise from the accumulation of alterations that occur directly in stem cells: CD133 +ve.

treatment resistance

treatment resistance

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Molecular Biology:

Growth factor receptors

Signaling pathways

RB pathway.

P53 pathway.

Tyrosine Kinases pathways: RAS-RAF.

PI3K

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Molecular Biology “promising agents”

EGFR

1) Over-expressed: 50% of GBM.

2) Del of exon 2-7 “loss of extra-cell domain”: (mutant EGFRvIII)

• 30 % of patients

• Poor prognosis.

• Celldex intradermal vaccine (Rindo pepi mut).

• Phase II study, ACT III trial, SNO 2010, 65 pts with newly diagn GBM,

• Taken for 3 months with adjuv TMZ.

• Median survival ~ 22 ms (compared with 15 m in EORTC/NCIC study)

Now ongoing:

Phase III Study of Rindopepimut/GM-CSF in newly Diagnosed GBM; (ACT IV). ClinicalTrials.gov Identifier: NCT01480479

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Cilengitide:

• Anti-integrins: which is important for angiogenesis.

• I.V. drug.

• Newly diagnosed GBM:

Phase II trial, (Burt Nabors, Cancer2012;118:5601-7, Nov 2012)

Combined with RT + TMZ.

OS was ~20 months.

Patients with MGMT promoter methylation tend to show a higher PFS and OS (~30 ms).

• Now ongoing:

CORE study, phase II (NCT00813943)

Clinical trial testing the efficacy of cilengitide with TMZ + RT in patients with or without

MGMT methylation.

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Cediranib:

• Oral pan-VGEFR TKI

• Recurrent GBM:

As a single agent (phase II): showed a PFS ~ 4 ms and OS was ~

7.5 ms

A phase III trial with cediranib + lomustine for the treatment of

recurrent GBM in currently ongoing (NCT00777153).

• Newly diagnosed GBM:

All clinical trials are currently ongoing or recruiting:

Phase I/II cediranib + RT + TMZ (NCT01062425 and NCT00662506);

Phase I combination with BVZ (NCT00458731);

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What is the standard of care for GBM?

adjuv.

Concurrent Surgery

RTx

TMZ

TMZ

Age ≤ 70

PS ≤ 2

Surgery: max safe resection.

RTX: 60 Gy, fractionated, partial brain.

TMZ: Temodar.

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EORTC/NCIC

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EORTC/NCIC

RAND

After Surgery

• 573 pts.

• GBM.

• Age ≤ 70

• PS ≤ 2

RTX alone

RTx+TMZ then adjuv TMZ

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EORTC/NCIC methodology:

Radiotherapy :fractionated focal irradiation ,2 Gy per fraction given once daily 5 days per week over 6 weeks; (total dose of 60 Gy).

Concomitant chemotherapy: temozolomide 75 mg /m2 daily. from the first day of radiotherapy until the last day, (no longer than 49 days).

Adjuvant temozolomide: 6 cycles of 5-day schedule every 28 days; 150 mg /m2 for the first cycle and was increased to 200 mg /m2 beginning with the second cycle.

patients in the radiotherapy plus temozolomide group were to receive prophylaxis against Pneumocystis carinii pneumonia, consisting of either inhaled pentamidine or oral trimethoprim–sulfamethoxazole

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•At least 2 weeks of Cortz.

Before randomization.

•About 70% were on Cortz.

About 16% had just Biopsy..

About 70% were ≥ 50 years

subgroup with no

survival benefit

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EORTC/NCIC Results:

2-year survival rate

27 % with

RTx + TMZ

10 % with

RTx alone.

5-years: 10.9 %

5-years: 1.9 % Median survival benefit=2.5 m;

From 12.1 m to 14.6 m with RTx-TMZ

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TMZ did not increase risk

of treatment delay or interruption

Median time from diagnosis to the

start of treatment was 5 weeks

85 % completed concurrent

RTx-TMZ

78% started adjuv TMZ

47% completed 6 cycles

Main reason was

disease progression

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EORTC/NCIC Results:

Grade 3 or 4 hematologic toxic effects: • Concomitant RTx + TMZ: 7 % of patients.

• RTx alone: 0 %

• Adjuvant TMZ: 14 %

A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60–70 years.

Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy

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Critic:

Benefit from

Concomitant RTx-TMZ

Adjuvant TMZ

OR

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MGMT O-6-methylguanine-DNA methyltransferase.

DNA repair enzyme.

Function: repair the damage of DNA caused by alkayting agents e.g TMZ.

When methylated: it dose not work.

Methylated cases: better response to TMZ, better PFS and OS.

This was illustrated in the update of EORTC/NCIC trial in 2009, and both NOA-08 and the Nordic trial of TMZ in elderly GBM pts.

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Evidence- based medicine:

Concurrent Surgery

TMZ

RTx

TMZ

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Concurrent Surgery

TMZ

RTx

TMZ

Benefit of RTx :

Dose of RTx :

Fx of RTx :

Stereo. boost:

Dose-dense

TMZ

Avastin

BTSG MRC RTOG9006 RTOG9305

RTOG0825 AVAglio GLARIUS

RTOG0525

Old age

Nordic NOA-08

Canadian Frensh

Evidence- based

medicine:

BCNU-wafer Neuro-onc J

2003, Phase III

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BTSG, 1978:

ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

MRC, 1991:

474 pts randomized to 45 Gy vs 60 Gy increase surv from

( no chemo) 9 to 12 ms. With 60 Gy

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RTOG9006, 1998:

222 pts.

90% GBM RAND

• Observ.

• BCNU.

• RTx alone.

• RTx +BCNU. Increase surv: 3-6 ms

712

pts. RAND

• 60 Gy:

(2Gy/Fx)

• 72 Gy: (1.2Gy BID)

Better survival

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RTOG0525, 2011-JCO:

823pts.

KPS≥60 RAND

• Standard TMZ dose

• Dose-dense TMZ.

No difference in both OS &

PFS.

Increase toxicity with dose-

dense

After

RTx

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Canadian trial, 2004-JCO:

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French trial, 2007-NEJM:

100 pts.

GBM

age≥ 60

KPS≥ 50

RAND

•RTx 60 Gy.

• 40 Gy/ 15 Fx (3 Ws)

Same OS ;

5.5 ms. decrease need

to inc Cortz dose

with 40 Gy

85 pts.

G III & IV

age≥ 70

KPS≥ 70

RAND

• RTx (50 Gy/ 1.8 Gy)

•BSC

Significant

inc of

survival

Critic: underpowered statisticaly

GBM in elderly

more than 44% of GBM

occcur in pts > 65 ys.

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Nordic (NCBTSG), 2012-Lancet onc:

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German (NOA-08), 2012-Lancet onc :

“non-inferiority study”

342 pts.

GBM

Age > 60

Good PS

RAND

TMZ alone; 6 ms

vs

RTx 34 Gy/ 2Ws

vs RTx 60 Gy.

412 pts. GBM (89%)

Age > 65

KPS≥ 60

RAND

• RTx (60Gy/ 30 Fx)

•TMZ: Week on / week off

100 mg / m2

No

Significant

differences in

OS (~9 ms)

GBM in elderly

> Neutopenia in TMZ arm

Better

survival

when

compared to

60 Gy

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Avastin in GBM FDA approval in recurrent cases in 2009 based on 2 phase II

studies:

BRAIN trial, JCO 2009:

Phase II.

167 pts with Recurrent disease.

Avastin alone or with Irinotecan.

Avastin decreases the need to escalade the cortz dosage.

Intra-cranial Hge 4% with Avastin + Irino.

Grade ≥ 3: HTN (8%), convulsion (6%), fatigue (90%).

6ms PFS OS RR

Avastin 43 % 9 % 28 %

Avastin+Irinotecan 50 % 9 % 38 %

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Avastin in newly diagnosed GBM

Adding to standard of care

Compared with standard of care

GLARIUS trial

• JCO, 2013, Abstract

• Phase III

• ~ 170 pts.

• Non-methyl MGMT

Significant inc

In PFS with

Avastin + Irinotecan+RTx

vs

Standard of care

AVAglio trial

• JCO, 2013, Abstract

• Phase III

• ~900 pts.

Significant inc

In PFS with

addition of

Avastin to

Standard of care

RTOG 0825

• JCO, 2013, Abstract

• Phase III

• 637 pts.

Significant inc

In PFS with addition

of Avastin to

Standard of care

Inc GIII toxicity with

Avastin.

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Novocure (TTF):

• Uses electric fields within the human

body that disrupt the rapid cell division

exhibited by cancer cells.

• Disrupt mitotic spindle microtubule

assembly and to lead to dielectrophoretic

dislocation of intracellular

macromolecules and organelles during

cytokinesis.

• Affect only one cell type at a time; The

frequency used for a particular treatment

is specific to the cell type being treated.

• TTF therapy has not been shown to

affect cells that are not undergoing

division.

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Novocure (TTF): ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ FDA approval in 2011 for recurrent cases of GBM based on

phase III study:

Stupp et al, Eur J cancer, 2012

237 pts with recurrent disease.

Rand to TTF vs Chemo.

Result was same survival.

Low toxicity with TTF + imroved QOL.

Now ongoing trial for adding TTF to standard of care in newly diagnosed cases. (NCT00916409)

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Gliadel wafers:

• Implantation of BCNU-wafers in the surgical cavity

intraoperatively.

• Significantly improve survival in recurrent cases

(Brem et al, Lancet 1995).

• In a phase III trial from Germany, which was

published at the neuro-oncology journal in 2003, 240

newly diagnosed pts showed significant improvement

in median survival from 12 m to 14 ms after

implantation of BCNU-wafers then RTx ( no adjuv

systemic chemo).

• FDA approved in new cases.

•Toxicity:

CSF leak 5%

I.C.HTN 9 %. .

Which is not the standard of care

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Anaplastic Gliomas ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas.

Would you treat it typically as the GBM ??

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Resection appears to improve survival relative to biopsy, as it does for

GBM.

Addition of chemo to Rtx. failed to improve survival in 2 phase III trials: (unlike GBM)

Co-deletion of 1p 19 q correlates with better response to chemo.

Adjuvant temozolomide was as effective and less toxic than PCV in anaplastic astrocytoma, based on one retrospective study. (?)

Rationale for the ongoing CODEL trial.

RTOG 9402 and EORTC 26951

Rationale for the ongoing RTOG 9813 trial.

Should be investigated in pts with poor prognosis ( non co-deleted):

Rationale for the ongoing CANTON trial.

What bout using CTx. alone as adjuvant ?

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RTOG9402, 2006-JCO :

after surgery

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EORTC26951, 2006-JCO:

after surgery

289 pts.

Anaplastic

oligodendr.

RAND

PCV X 4 then Rtx.

RTx alone (60Gy)

Same OS

PCV

increase PFS

Benefit with

co-deleted pts.

368 pts.

Anaplastic

oligodendr.

RAND

• RTx then PCV X 6

•RTx alone (60Gy)

No diffr. in OS

Increase PFS

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NOA-04, 2009-JCO:

• Survival rates were equivalent whether chemotherapy or radiotherapy was used

first among patients with anaplastic astrocytomas, oligodendrogliomas, and mixed

tumors.

• Time to progression following RT was longer than after chemotherapy.

• Initial radiation therapy achieved more complete and partial responses than initial

chemotherapy.

318 pts.

Anaplastic

glioma

RAND

• RTx

•PCV

•TMZ

Progression • Chemo.

•RTx

•RTx

Suggesting the superiority of radiotherapy.

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The ongoing CATNON (Concurrent vs. Adjuvant Temozolomide for

NON 1p19q co-deleted anaplastic gliomas)

It will answer 2 questions:

• Benefit of add CTx in non co-del anaplastic glioma.

• Concurrent vs adjuv TMZ (? In EORTC/NCIC trial).

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CODEL; (for 1p/19q CO-DELeted tumors):

Randomizes patients to:

RT alone.

RT with concurrent and adjuvant temozolomide.

Temozolomide alone.

To prospectively address the issue of CTx alone in co-deleted

patients.

RTOG 9813 :

Randomized patients with anaplastic astrocytomas (or

oligoastrocytomas) to:

Radiotherapy with concurrent nitrosourea; (carmustine or lomustine).

Radiotherapy with concurrent temozolomide.

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What is the standard of care for

anaplastic glioma ?

Surgery RTx

TMZ

PCV

Surgery: max safe resection.

RTX: 60 Gy, fractionated, partial brain.

PCV: Procarbazine+CCNU+Vincristine

If co-deleted

or

concurrent

Good PS

Before or

after RTx.

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The standard of care of newly diagnosed GBM cases is

Surgery then concurrent RTX/TMZ then adjuvant 6 cycles

TMZ.

Some new and promising trends will be based on

molecular targets.

The standard of care of newly diagnosed anaplastic

glioma cases is surgery followed by adjuvant RTx, and if

co-deleted you can add adjuvant chemo.

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