low grade gliomas the non surgical management of ...€¦ · – hypertension, kidney problems,...
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The non Surgical Management of Paediatric
Low Grade Gliomas
Eric BouffetGarron Family Chair in Childhood Cancer Research
The Hospital for Sick ChildrenToronto
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
num
ber
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
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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
Long history (several months)
Mostly vomiting and headaches
Well circumscribed tumour
Rim enhancement
Neuro-navigation
Fonctionnal Mapping
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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,behaviouralchanges
Surgery for hypothalamic gliomas
Management of paediatric LGG
• Main issue:– Management of
unresectable low grade gliomas
– Management after biospy/incompleteresectionObservation (betting game)Treatment (Which one? When? Why?)
Post resection 3 months later2001
4 year-old, NF1
2002
No change in vision
No treatment
2003
Treatment or not?
2014
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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 2001January 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 ++)
LGGTarget Volumes
Gross Tumour Volume (GTV)
Clinical Target Volume (CTV)
Planning Target Volume (PTV)
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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)
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Feb 2003:
start chemo
May 2003 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 a risk of neurologic impairment
Why?
• Aims of treatment – Response– Visual preservation (optic pathways)– Delay of radiation treatment– Cure/Survival– Minimize morbidityLGG: 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 vincristine inrecurrent 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
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1997: Update on Vincristine-carboplatin (Packer)1997: Update on Vincristine-
carboplatin (Packer)
NF1
1997: Update on Vincristine-carboplatin (Packer)
Response to chemotherapy
Canadian review of allergic reactions to Carboplatin :
105 patients
Cumulativeincidence of allergicreactions: 41.9%
Lafay-Cousin,Cancer 2007
COG 9952 Carboplatin allergy
– CDDP 90 mg/m2 and etoposide 450 mg/m2 for10 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 year-old 33 vs 87% EFS, less than 5 year-
old 66 vs 100%)• Response not prognostic
– 28% hearing loss
2002: Cisplatin-etoposide (Massimino)
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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?
LOW GRADE GLIOMAPATIENTS TREATED WITH 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
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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 2003June 2003 (71%)
Clinical progressionOff study?
Feb 2004 Feb 2005 (end of treatment)
Diagnosis7 year old
(largechiasmatic
glioma)
Progression 5 months after completion of
vincristine-carboplatin
May 2007
Phase II study of vinblastine
9952
First line38% at 5 years
Vinblastine
Second line43% at 5 years
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Admission Vinorelbine – 18 Cycles Observation
Progression
Descontinue the drug
Initial
4 cycles
0
2
4
6
8
10
12
14
nov/09dec/10jan/10 feb/10mar/10
__ weight
4y boy, Diencephalic S.nystagmus, vomiting and
no weight gain
Initial
4 cycles
8 cycles
4m girl, diffuse brainstem tumor;swallowing difficulties and mechanical
ventilation dependent; biopsy
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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
The BRAF-KIAA1549 (B-K) fusion gene
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The BRAF-KIAA1549 (B-K) fusion gene
trametinib
trametinib
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Avery et al, JAMA Ophthalmol 2014,
150 paediatric patients, to start in 2015
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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%
Rationalefor
ACNS1022
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
End of treatment 3 months later
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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.aEverolimus starting dose 4.5 mg/m2/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
Placebon = 39
RANDOMIZE
Crossover at SEGA progression
Treatment until SEGA progression or unacceptable toxicity
Stratified by EIAED use
Progressive SEGAassociated with TSC (N =117)Definitive TSC per Gomezcriteria1 target SEGA lesion 1 cmin diameter
Serial SEGA growthconfirmed by imaging ornew/worseninghydrocephalus
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 60Placebo EverolimusIn favor of
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)
Everolimus0/39 (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
Dosesbelow 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.”
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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
Vemurafenib in refractory ganglioglioma
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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
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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 PD184352Microtublule destabilizing agent TZT 1027
Questions
• Assessment of response– No consensus– Urgent need for harmonization– Issue of “pseudoprogression”– Time of response
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Start of therapy(dabrafenib) 2 months later
CompleteResponse
Stabledisease
No consensus: T1? T1 +C? FLAIR? T2?
Skrypek et alPBC 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