Paediatric Brain Tumour: where are we today with treatment and where should we be tomorrow?

Rakesh Jalali

Professor, Neuro-Oncology Group

Tata Memorial Centre

Mumbai, INDIA

Paediatric Brain tumours: disease burden, facts,

challenges…..

• Global incidence is 3-5 per 100,000 person-years

•2nd most common neoplasm in childhood (after

leukemia)

•Leading cause of death from childhood cancers

worldwide

•Leading cause of cancer disability in children and

young adults

• Mandates Multidisciplinary Team Effort: clinicians, radiologists, pathologists, basic

scientists, occupational therapists, psychologists, rehab team, social workers

• Administration, public/society at large

• Rehabilitation, social functioning and quality of life, patient reported outcomes, palliative

care, long-term survivorship issues : extremely relevant

Medulloblastoma: Commonest Paediatric Brain Tumour

2 year Survival: 50-100%

5 year: 70-95 %

Medulloblastoma – Grade IV Glioblastoma – Grade IV

2 year: 25-30%

5 year: 10 %

Medulloblastoma: Optimising treatment Balancing between cures and long term toxicities

• 75-90% cures in average risk, 20-50% in high risk

• Neurocognitive and endocrine dysfunction

• Ototoxicity, CVA and vasculopathies

• Second malignant neoplasms

• Needs more robust risk stratification based on

molecular profiling and clinical data

Feature Average-risk High-risk

Age ≥3 yrs <3 yrs

Residual Tumor ≤1.5 x 1.5 cm2 >1.5 x 1.5 cm2

Metastases None (M0) Present (M1-M4)

Pathology Desmoplastic / MBEN Large cell / Anaplastic

MYC (C-MYC/N-MYC) Low Amplified

Molecular subgroup WNT Group 3

• Need for 2nd look to lower the risk category

• Need for immediate post op scans with experienced neuro-radiologist

• Recognition of post op mutism/post fossa syndrome

• Molecular profiling

Molecular profiling of Medulloblastoma

Northcott et al, JCO 2010

Nuclear B Catenin - favourable MYC C/N amplification - unfavourable

Revolutionary

Molecular classification: international consensus

IHCTissue micro array Nanostring DNA Methylation MicroRNA’s

Validation of German tumour samples

Can we predict subgroups on MRI? TMH Radiogenomics study (n=130)

• Overall accuracy is 67%

• SHH were predicted correctly in 95% cases

• Presence of peri-tumoural oedema, cystic degeneration, superiorly placed

tumours touching the tentorium

• Group 4 : 75% accuracy

• WNT tumours midline/towards CP angle

Dasgupta et al ISPNO 2016

Further evolution: Current ConsensusRamaswamy et al, Acta Neuropathol 2016

LR: Low Risk

SR: Standard Risk

HR: High Risk

VHR: Very High Risk

VLR and LR: De- escalation of therapy

HR and VHR: Escalation and novel therapies (targeted therapies for some SHH)

St Jude’s / COG study

• Lowering CSI dose to 15 to 18 Gy

• Minimise chemo during CSI

• Reduce platinum doses; only 4 cycles

• Small residual: still Low risk

TMC, Mumbai trial (protocol just approved by IRB; due to start 1st July 2017)

• No CSI: only localised tumour bed RT + chemoFOR-WNT trial

• MRI Brain and spine post RT 3 monthly for first 2 years

• Strict stoppage rule (60 patients)

• Could be a practice changing trial

• Prospective evaluation of neurocognitive and endocrine function

Towards De-escalating therapyWNT pathway medulloblastoma in children: 90-100% long-term cure

? Less aggressive/morbid surgery : they tend to be midline/towards CP angle

Paediatric Gliomas

• Most common group of paediatric brain tumours

• Most common is Low Grade Glioma

– High grade glioma 8-12% only

– Do not transform like adult diffuse (low grade) gliomas

• Heterogeneous Bag of pathologies, location, presentation, etc

Pilocytic astrocytomas– BRAF mutation and BRAF

fusion • 8 year old boy, headaches and ataxia of 2 months duration

• Outside HPR Oligo - Gr II, GFAP +ve, Ki 67:7-8%

• Referred for adjuvant Rx

Pilocytic astrocytoma

IDH1R132H - Negative

MIB-1 labeling index - 3-4%

BRAF Fusion (KIAA1549): Positive,

Clinches the diagnosis

• BRAF Fusion (positive /diagnostic of pilocytic astrocytoma)

• BRAF V600E mutation (mainly positive in PXA and ganglioglioma)

BRAF inhibiters (targeted agents)• mTOR inhibitors (Rapamycin, Everolimus)

• PI3K inhibitors, dual mTOR/PI3K inhibitors

Pleomorphic Xanthoastrocytoma (PXA) – impact of WHO 2016 and BRAF

• TMH experience (2006 to 2016)

• 60 patients identified

• Path reviewed in all

• 37 patients formed study cohort

• 5 patients with PXA gr II were upgraded to

anaplastic PXA gr III based on WHO 2016 update

•PXA is a grade II glioma seen primarily in children

and young adults

• BRAF V600E mutation in nearly 50-60%

•Anaplastic PXA

-Mitotic index ≥ 5/10 HPF

-with or without presence of necrosis

-Endothelial proliferation

Paediatric Glioblastoma

• Relatively rare (<5% ) incidence

• Median suviva l- 15 months

• Biologically distinct lesions from their adult counterpart

• No uniformity in the choice of the chemotherapy regimen

• Non EGFR amplified

Ongoing trials –

•DC vaccine

• Immunotherapy – viral therapies

•Novo TTF

•Dabrafenib with Trametinib

Diffuse Pontine Gliomas - diffuse midline gliomas

• Most common type of brainstem glioma (>80%)

• Median survival 10-12 months; 2-year survival around 5-8%

• Biopsy difficult due to location

• RT provides early and durable symptomatic relief

• H3K27 Mutation seen in 80% cases• Characterized by K27M mutations in the histone H3 gene

H3F3A, or less commonly in the related HIST1H3B gene

Molecularly Determined Treatment of Diffuse

Intrinsic Pontine Gliomas (DIPG)

This study is ongoing

Institute - Dana-Farber Cancer Institute

Targeted therapy in Pediatric Brain Tumours

Natural Killer (NK) Cell Infusions

• Haploidentical NK cell infusions have been shown to

maintain remissions in children with acute leukemia

Ongoing trials

1) Use of allogenic NK cells in recurrent Medullos, ATRT, GBM

2) Use of CAR-T cells in Recurrent Pediatric Brain TumorsPD1/PDL1 inhibitors

Pidizumab

Nivolumab

Pembrolizumab

Atezolizumab

Sustained response up to 7.5 months

Next 5-10 years will be devoted to Immunotherapy

Possible minimisation of dependency/need of conventional radiotherapy and chemotherapy

• Medulloblastoma – high risk with mets to spine

• Treated in 2009, Novel protocol of CSI +concurrent

carboplatin

• Completed his education, business

administration

• Upcoming confident young man

Similar several long time survivors, leading normal/near normal lives

With permission

Focus on Survivorship

Feb 2017

2009 2014

Pontine necrosis / vascular changes

With permission

• Childhood Cancer Survivor Study, N >10,400

• 63% have at least 1 chronic medical issue; 27% severe/life threatening

• Higher incidence and severity of chronic diseases in CNS survivors

Chronic Health Conditions: Long term survivorship

Oeffinger et al, NEJM 2006

Problems with -

↓ Thinking

↓ Learning

↓ Remembering

Neuro cognitive dysfunction – Long known, Most visible

Verbal/nonverbal cognition declined to

one SD below mean in CNS survivors (Robinson et al, PBC 2010)

• Intellectual function in CNS

survivors (6-17 years)

• Worse function in

▪ Lower social economic status

▪ Cranial RT

▪ Younger age at diagnosis

▪ Supratentorial tumour

location

Butler et al, 2013

Second Malignant Neoplasms

Armstrong GT et JNCI 2009

Cerebrovascular Accidents / post Rx Vascular events

• Rate of late-occurring stroke in CNS

survivors 267 per 100,000 person-

years

• RR = 29 as compared with siblings (p

= 0.0001)

• Increased risk with mean cranial RT 30

Gy or above

Bowers et al, JCO 2006

Temporal lobes importantPossible role of hippocampus,

frontal lobes etc

Neuroendocrine Deficits

Merchant et al, IJROBP 2002

▪ Peak GH decline 0-12 months post cranial RT

▪ Largest effect with 40–60 Gy RT

▪ Also impacted by tumour location, number of

surgical interventions and hydrocephalus

BTF project on Growth hormone supplementation support (n=83; more that 2.1 crores)

0

10

20

30

40

50

60

6 m 2 y 3 y 4 y 5 y

Pe

rce

nt

difference in slope= 0.047; P=0.0112

Adolescents and Young Adults (AYA)

Unique challenges

• Brain tumours are 2nd leading cause of cancer

death in males and 5th in females aged 20-39

•The National Institute of Health (NIH), standard

age AYA group as 15-39 years • Diagnosis at a relatively advanced stage

• Biologically distinct from that of children

or adults

• Only 2%-5% enter in clinical

trialsBody image in Adolescents and Young Adults (AYA)

• Fatigue and somnolence: less participation in

physical activities

• Growth disturbances

• Alopecia

• GI disturbances

• Weight loss/gain • Impaired fertility- emotional and psychological

distress

• Sexuality- dissatisfaction with ‘ideal self’,

perception of rejection

Evolution in therapy - has it improved survivorship?

Armstrong et al NEJM 2016

Can long term survivorship issues be suitable endpoints for testing new

interventions in neuro oncology?

Medical Endpoints• Cognition / endocrine

• Stroke/vascular events

• SMN

• Growth

• Psychological /psychiatric issues

A Phase II Trial of Limited Surgery and Proton

Therapy for Craniopharyngioma or

Observation After Radical Resection

Institution - St. Jude Children's Research Hospital

Primary Objective

• PFS and OS

• Necrosis, clinically significant vasculopathy, and

permanent neurological conditions or deficits

Social endpoints (futuristic)

• Probability of employment

• Personal relationship

• Financial and social independence and long-term stability

Global burden of paediatric cancers

• 240,000 cases of children’s cancer

• Global cure rate 35%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Developing Developed

cases

Resources

Cure rate

Country No. per neurosurgeon

Australia 163,000

Japan 50,400

S Korea 58,100

Singapore 176,000

India 1,620,000

Bangladesh 3,630,000

Philippines 1,160,000

Facilities / ResourcesIndian and ASNO: diverse set ups

• India: Strong Neurosurgery fraternity with excellent

expertise all across the country, 2000 members

• Availability of high-end instrumentation and OT’s even

in moderate sized hospitals

• Uninhibited access to cadaver specimens

• Need to overcome nihilism for brain tumours

• Joint neuro-oncology forums / groups

• Need for more surgeons

Linear accelerators 400

Telecobalts 300

IMRT 250 facilities

Gamma Knife 6

SRS/SRT (LA based) 40-45

Tomotherapy 6

IGRT (cone based) 100

Cyberknife 6

VMAT 50

Protons 2 (due in 2018-19)

< 0.2 machines / million population

0.2 – 0.4 machines / million population

0.4 – 0.6 machines / million population

> 0.6 machines / million population

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Distribution of Teletherapy Machines: India

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< 0.2 machines / million population

0.2 – 0.4 machines / million population

0.4 – 0.6 machines / million population

> 0.6 machines / million population

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Distribution of Teletherapy Machines: India

December 2005

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• Developing countries account for 85% of world’s

population

• Developed countries account for 15% of the

population with 85% of radiation facilities

Radiotherapy

• Current incidence of cancer in developing low-middle income countries (LMIC): 8 million per year

• Current radiotherapy units needed: 9,600

• Current supply: 4,400

• Current Shortage: 5,000

Facilities in some developing countries

South Asia

North Africa

https://dirac.iaea.org

Southern Africa

Southeast Asia

World Health statistics 2013

1.04% of GDP spent on Public Health Out-of–pocket : 61% of total health expenditure

Diversity in cancer care in childhood cancers

• Financial support (investigations, therapy, rehab, education)

• Growth hormone supplementation support (n=82)

• Molecular markers on tumour tissue blocks for needy patients throughout the country

• Monthly support group meetings (since 16 years)• Information on Brain Tumours through a booklet

GUJRATI ORIYA

BTF India Annual Art Festivals; as a part of IBTA International Brain

Tumour Awareness Week; every year(15th Oct 2017)

Bust that noma (youtube)