Low grade gliomas. The non Surgical Management of Paediatric Low Grade Gliomas. Paediatric low grade glioma is not a single entity

(1)

The non Surgical

Management of Paediatric

Low Grade Gliomas

Eric Bouffet

Garron Family Chair in Childhood Cancer Research The Hospital for Sick Children

Toronto

Low grade gliomas

• Most common paediatric brain tumour • Includes grade I and grade II astrocytic

tumours (aka: benign gliomas, low grade astrocytomas…)

• Can arise anywhere in the CNS

All LGG!

Paediatric low grade glioma is not a

single entity

Paediatric low grade glioma is not a

single entity

Low Grade Glioma in children

0 5 10 15 20 1 3 5 7 9 11 13 15 17 Age nu m b e r OPG PF

Pathology of Paediatric Low Grade

Gliomas

• Grade 1 or Pilocytic • Grade 2 – Pilomyxoid – Fibrillary – Others Biphasic Pattern Smear Slide Rosenthal Fibers Vessels in JPA

(2)

Predisposing conditions

• Neurofibromatosis type 1 JPA • Tuberous sclerosis SEGA

Behaviour of paediatric LGG

• Highly variable • Reasons still unclear • Can even disseminate

• However, with some exceptions (thalamic tumours), do not show malignant

transformation (unlike adult LGG)

Treatment of paediatric low grade

gliomas

• Complex equation!

Site_*Operability_*histology

=

(behaviour)4/3

Management of paediatric LGG

• Surgery +++

• Surgery is curative for the surgical lesions (cerebellar astrocytomas)

• Surgery is still the mainstay of treatment for most other LGGs

Low grade glioma, cerebellum

¾Long history (several months)

¾Mostly vomiting and headaches

¾Well circumscribed tumour

¾Rim enhancement

Neuro-navigation

(3)

Tectal Tumors in Children

• CSF diversion best accomplished by endoscopic third ventriculostomy • Excellent results even in young children • No other treatment

Surgery for low grade glioma in

critical areas

• Optic pathways • Brainstem • Spinal cord • Thalamus • Various schools

– From observation to aggressive surgery – Be aware of the competition (shopping

around)

Blind, DI, swings with temperature, Hyperphagic, behavioural changes

Surgery for hypothalamic gliomas

Management of paediatric LGG

• Main issue: – Management of unresectable low grade gliomas – Management after biospy/incomplete resection ÆObservation (betting game) ÆTreatment (Which

one? When? Why?)

Post resection 3 months later

2001 4 year-old, NF1 2002 No change in vision No treatment 2003 Treatment or not? 2014

(4)

Treatment or not?

2006

6 year-old, neck plexiform neurofibroma

2007 6.5 year-old Second case (NF1)

Treatment or not?

2006 6 year-old 2007 6.5 year-old August 2001 August 2011 Treatment or not? August 2000 December 2001 January 2000 Treatment or not?

Non surgical management of

paediatric LGG

• Radiation and chemotherapy: an unsettled and absurd competition

• Traditionally, radiation is the standard treatment • But, who would systematically use up-front

radiation in a population of patients with a survival rate > 95% at 10 years and a close to normal life expectancy?

– Risk of stroke (RR: 70 at 15 years, CCSS)

– Risk of secondary brain tumour (RR: 6.7 at 5 years, SEER)

– Endocrine deficits

– Decline in cognition (younger ++)

LGG

Target Volumes

Gross Tumour Volume (GTV) Clinical Target Volume (CTV) Planning Target Volume (PTV)

(5)

Outcome for All Clinically Relevant PLGG Patients by Upfront Radiation Therapy Outcome for All Clinically Relevant PLGG

Patients by Upfront Radiation Therapy

p<0.0001

36/717

46/154

Long Term OS by Tumour Location

p<0.0001

• Thalamic tumors demonstrate unique pattern of very late death (> 10 years of follow up)

Thalamic Brainstem

Management of paediatric LGG

• Chemotherapy:

– After failure of radiation (historically) – Then for young children only

• 5 year old (SIOP)

• Then < 10 year old (North America)

At progression

(after partial resection) 12 month later 12 month of vincristine-carboplatin

Aug 2001

Dec 2001

Feb 2003 (end of treatment)

(6)

Feb 2003: start chemo May 2003 Æ blind Jan 2005: end chemo

2 ½ year old child, no NF1

Management of LGG:

When should we treat?

• COG recommendations (COG 9952)

• Still unclear:

– Who are the candidates for upfront treatment – What is 䇾a risk of neurologic impairment䇿

Why?

• Aims of treatment

– Response

– Visual preservation (optic pathways) – Delay of radiation treatment

– Cure/Survival – Minimize morbidity

ÎLGG: a chronic disease?

Which treatment?

Are there better recipes?

Should we take into account other factors?

Chemotherapy for paediatric LGG

• First publication in 1976 (pre CT era): broad phase II study of vincristinein recurrent brain tumours

• Then in 1988 Vincristine-actinomycin (Packer) • In 1993: Vincristine-carboplatin (Packer) • In 1997: TPCV (Petronio-Prados)

1997: Update on

Vincristine-carboplatin (Packer)

• 78 patients (15 NF1) • Mean age: 3 year • tumour site:

– Hypothalamic/chiasmatic: 58 – Brainstem: 12

(7)

1997: Update on Vincristine-carboplatin (Packer)

1997: Update on

NF1

1997: Update on

Response to chemotherapy

Canadian review of allergic

reactions to Carboplatin

:

105 patients Cumulative incidence of allergic reactions: 41.9% Lafay-Cousin, Cancer 2007

COG 9952

Carboplatin allergy

– CDDP 90 mg/m2_{and etoposide 450 mg/m}2_for

10 cycles

– 34 patients (29 hypothalamic/chiasmatic – 8 NF1 – median age 45 months)

– 3 year-EFS: 78%, OS: 100%. – Prognostic factors:

• NF1 (no progression)

• Age (< 1 old 33 vs 87% EFS, less than 5 year-old 66 vs 100%)

• Response not prognostic – 28% hearing loss

(8)

Italian Study

Temozolomide

(CCG phase II study)

• 5 day schedule (q 4 w)

• 21 patients, 20 evaluable

• All recurrent (no information on prior therapy)

• Response:

– 1PR, 9 sustained SD, 10 PD

Temozolomide in Paediatric LGG

Gururangan 2007

SIOP-CCG: which one is the best?

LO W G RADE G LIO M A

PATIENTS TREATED W ITH CT

Progression Free Survival

N. pts N.failed % of survival at 3 years 155 43 48.7 (34.5 - 62.9)

3 y PFS : CCG (68 %) 3 y PFS : SIOP (48 %)

Carboplatin : 560 mg/m2_{/4 weeks} Vincristine : 1.5 mg/m2_{/4 week (20)} More transfusion, as many allergic reactions Carboplatin : 175 mg/m2_/week Vincristine : 1.5 mg/m2_{/week (46)} (COG 9952: 34 x Vcr)

COG 9952

TPCV versus Vincristine-carboplatin A = vincristine-carboplatin B = TPCV Good = NF1, small tumours Bad = young, large tumours

COG 9952 and other studies

Most children will require more than one line of treatment!

EFS is 38% at 5 years

(9)

New Recipes

• Vinblastine • Vinorelbine

• Bevacizumab based regimens • mTOR inhibitors for SEGA

Vinblastine

• Phase II study initiated in October 2000 • Eligibility:

• relapse/progression after previous chemo or irradiation

• Schedule: 6 mg/m2_/week

• First assessment: between week 10 and 12 • Duration: 52 weeks October 2000 March 2001 Jan 2001 Jan 2002 Dec 2002 (end of VBL) June 2005

Continued GH treatment during vinblastine!

March 2003

June 2003 (71%) Clinical progression

ÆOff study?

Feb 2004 Feb 2005 (end of treatment) Diagnosis 7 year old (large chiasmatic glioma) Progression 5 months after completion of vincristine-carboplatin May 2007

Phase II study of vinblastine

9952 First line 38% at 5 years Vinblastine Second line 43% at 5 years

(10)

AdmissionVinorelbine– 18CyclesObservation

Progression

Descontinuethedrug

Initial 4cycles 0 2 4 6 8 10 12 14

nov/09dec/10 jan/10 feb/10mar/10

__ weight 4yboy,Diencephalic S.

nystagmus,vomitingand

noweightgain

Initial

4cycles

8 cycles

4mgirl,diffusebrainstemtumor;

swallowingdifficultiesandmechanical

(11)

What can we learn from previous

experiences

• Most children will need more than one treatment

• So, oncologists need to think ahead of time • Most unresectable paediatric low grade

gliomas cannot be cured with one shot • This is

A CHRONIC DISEASE

First and second line of chemo

• No clear evidence of acquired resistance to chemotherapy • Event free survival similar between first and second line

chemotherapy • EFS is in the range of 40% at 5 years. Scheinemann et al, PBC 2011

Additive/cumulative toxicity

• Carboplatin/vincristine-carboplatin – Allergic reactions • TPCV – Hematological toxicity – Risk of secondary cancer – Infertility

• Etoposide-cisplatin – Hearing loss – Risk of leukemia • Temozolomide

– Still poorly known (second cancer?) • Vinblastine, vinorelbine

– No long term toxicity • Bevacizumab-based

– Hypertension, kidney problems, growth issues

Cost

• One year of – Vincristine-carboplatin: $ 1650 (CCG schedule) – Temozolomide: $ 19320 (12 x 5 d cycles) – Vinblastine: $ 1090 (weekly) – Vinorelbine: $ 2300 (weekly)

– Bevacizumab based: $ 60,000 (biweekly)

Fishing for the magic bullet

1 CR, 4 PR (573 patients) LGG: 35 patients, 2 PR

(12)

The BRAF-KIAA1549 (B-K) fusion gene

trametinib

(13)

Avery et al,

JAMA Ophthalmol 2014,

(14)

Phase I study

• 51 patients (2-21, median 10 year-old) • Dose levels: 15-116 mg/m2_{/day x 21 days}

• 2 objective responses (one thalamic astrocytoma, one OPG)

• 12 month PFS for patients with LGG was 67+13%

Rationale for ACNS 1022 trametinib

nn Neurol 2006

• Rapamycin causes regression of astrocytomas in TSC patients

• 4/5 paediatric patients – 3, 5.5, 14.5, 15 years

– Headaches, nystagmoid eye movements, change in mental status

– All patients responded to Rapamycin with decreased SEGA sizes (3-5 months) – 23x20 18x13 mm – 10.2x12.7 7.3x9.9 mm – 13.7x23.4 8.1x13.7 mm – 66x50 58x42 mm > 50% mTOR pathway

Patient

2 y 9 y

Patient 1

3 months after Rapamycin

Patient

(15)

Everolimus for SEGA in TSC

• Prospective, open-label phase I/II • Jan 2007 – Dec 2008

• N=28 (17 male)

• Median age 11 years (3-34 y)

• Dose 3 mg/m2_{achieving trough levels}

5-15 ng per milliliter

Darcy A. Krueger et al, NEJM 2010

EXIST-1 Study

Accrual August 2009 -September 2010

EIAED = enzyme inducing antiepileptic drug.

a_{Everolimus starting dose 4.5 mg/m}2_{/day and adjusted to trough level of 5-15 ng/mL. Dose could be adjusted in cases of toxicity.}

ClinicalTrials.gov identifier NCT00789828.

2:1

Everolimus target trough 5-15 ng/mLa n = 78 Placebo n = 39 R A N D O M I Z E Crossover at SEGA progression Treatment until SEGA progression or unacceptable toxicity Stratified by EIAED use ProgressiveSEGA associatedwithTSC(N= 117)

DefinitiveTSCperGomez

criteria

ш1targetSEGAlesionш1cm

indiameter SerialSEGAgrowth

confirmedbyimagingor

new/worsening

hydrocephalus

SEGA Response Rate in

Subgroups

Difference in SEGA response rate

Stratum Sex Age All patients (N = 117) with EIAED (N = 22) without EIAED (N = 95) Male (N = 67) Female (N = 50) <3 years (N = 20) 3 – <18 years (N = 81) 18 years (N = 16) -20 0 20 40 60 Placebo In favor of Everolimus EIAED = enzyme inducing antiepileptic drug.

Exact 95% confidence interval obtained from the exact unconditional confidence limits.

27/78 (34.6) 4/15 (26.7) 23/63 (36.5) 12/49 (24.5) 15/29 (51.7) 3/13 (23.1) 21/55 (38.2) 3/10 (30.0) Everolimus 0/39 (0.0) 0/7 (0.0) 0/32 (0.0) 0/18 (0.0) 0/21 (0.0) 0/7 (0.0) 0/26 (0.0) 0/6 (0.0) Placebo Response n/N (%)

Franz DN, et al, Lancet, 2013

EXIST-1 Results

100% 86% Weidman et al, PBC 2015 inefficient Doses below 2.5 mg/m2 inefficient

Everolimus in Paediatric LGG

• Kieran, SIOP 2013

• 23 patients with recurrent LGG (3-17 year-old)

• 2.7 previous treatments • 4 PR, 13 SD

• “Incorporation of everolimus into frontline LGG therapy is being proposed.”

(16)

trametinib

BRAF Inhibitors

• Several BRAF inhibitors undergoing testing – GSK: Dabrafenib – Roche/Genentech: Vemurafenib – Genentech: GDC 0879 – Novartis: Encorafenib (LGX818) – Cellagen: PLX 4720

BRAF Mutation in paediatric and adult gliomas

Rush S, JCO 2013

(17)

Start of therapy

(dabrafenib) 2 months later

Previous surgery, chemo and radiation

Start of Dabrafenib _{2 months later} _{April 2015} _{June 2015} Compassionate BRAF V600E

inhibitor

trametinib

MEK Inhibitors

• Several MEK inhibitors undergoing testing

– Astra-Zeneca: Selumetinib – GSK: Trametinib

– Novartis: MEK162 – Pfizer: PD0325901 – Roche: GDC-0973

(18)

Selumetinib in LGG (ASCO 2014

)

• 39 patients mean age at study entry 13.1 (5.6-20.8) • 56% JPA, 23% Gliomas, others.

• Recommended dose: 25 mg/m2/dose

[TITLE]

Selumetinib in LGG

• Phase II ongoing: 6 strata (PBTC 029B)

MEK inhibitor PD184352

Microtublule destabilizing agent TZT 1027

Questions

• Assessment of response – No consensus

– Urgent need for harmonization – Issue of “pseudoprogression” – Time of response

(19)

Start of therapy

(dabrafenib) 2 months later

Complete Response -Stable disease / No consensus: T1? T1 +C? FLAIR? T2? Skrypek et al PBC 2014

Duration of treatment

• Vincristine-carboplatin (1993): 84 weeks • Reduced to 60 weeks in 9952

• Currently patients on MEK or BRAF inhibitors for more than 2 years

• Long term toxicity of these treatments unknown

Next steps

• Medical treatment of paediatric LGG is complex

• Still a role for chemotherapy

• Targeted treatment will be the future for most paediatric LGG

• Perhaps more role for early biopsies when targeted treatments are widely available