Neuro-oncology in AYAsJoint efforts are worthwhile……

Didier FRAPPAZ

Centre Léon Bérard, and IHOP Lyon, France

Didier.Frappaz@lyon.unicancer.fr

PLAN

• Epidemiology

• The patients

• The tumors

• Toxicity

• Compliance

• Strategies

• Multidisciplinary meetings…….

EPIDEMIOLOGY

From: American Brain Tumor Association Adolescent and Young Adult Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012Neuro Oncol. 2015;18(suppl_1):i1-i50. doi:10.1093/neuonc/nov297

Neuro Oncol | © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail:

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INCIDENCE/100,000

LAUSANNE-ANOCEF-

16.05.2014

EPIDEMIOLOGY

US cancer incidence from Surveillance, Epidemiology, and End Results

(SEER), 1975 to 1998, by CNS tumor type.Kieran M W et al. JCO 2010

8 %

6 %

19 %

64 %

THE PATIENTS

Misleading symptomsPineal Suprasellar Bifocal

11 pts 12 pts 17 pts

(10 G) (8 F) (12 G)

DUREE DES SYMTOMES 4 mths 24 mths 36 mths

Raised intracranial Pressure 100 % 46 % 39 %

Convulsions 9 % 8 % 5 %

ENDOCRINO

• Db Insipididus 9 % 62 % 100 %

• Growth delay 0 % 38 % 50 %

• precocious puberty 0 0 17 %

VISUAL

• Vision (diplopia, VF, VA) 55 % 54 % 22 %

• Parinaud 36 0 5

HYPOTHALAMIC Synd

• Frontal Synd 0 31 % 11 %

• Anorexia 0 38 % 28 %

• Memory 9 % 31 % 28 %

HARDENBERG IJROBP 1997 39:419-26

Gogtay PNAS 2004

Evolution of Gray matter

Hormonal changes

Seric hormonal levels during infancy to adulthood (Ua= arbitrary units)

BOYS GIRLS

Coincidence???…

THE TUMORS

Vadgaonkar CNS 2018

Type oftumour

Zhang et al., Nat Gen 2013

Médullo

KW. Pajtler, Cancer Cell 2015

EPendymomas

Pediatric brain tumors ≠ adult tumors

MEDULLOBLASTOMA

WHAT IS KNOWN?

Epidemiology

Biology

Optimal treatment

Long term side effects

+

+

+

+

+

+/-

?

?

Children Adults

Epidemiology

Children Adults

% of brain tumors 20% 1%0.5/106 adults

% Posterior fossa

Tumors40% 6%

WHO 2007 classification

Extensive Desmoplastic/ Classic Anaplastic, Large cell nodularity, nodular Anaplastic

Aggressivity

INFANTS CHILDREN ADULTS

10q-

TAYLOR 2012

4

3

SHIH JCO 2014Intra nuclear beta cathenin +

The tools are similar

Surgery

Increased Cranial Pressure

=> Shunt

MRI Brain and spine

SURGERY

Post op MRI 24 – 72 h

Lumbar CSF (cytospin) day 10-15

RESIDUE > 1,5 cm²And/or

CSF and/or spine +

High risk

RESIDUE < 1,5 cm²and

CSF and SPINE -

Standard risk*CCG 921 : Zeltzer (JCO 1999, 832)

Defining Clinical risk factors

36 Gy

54 Gy

36 Gy

Standard = Cranio-Spinal Irradiation

A

BC

D

EF

G

H

I

IQ loss due to supra tentorial RT

>7

Year

<7

Year

Mulhern J Clin Oncol 2OO5, 23:5511-5519.

CSI 23 Gy CSI 36-39 Gy

(- 0.42

/year)

(- 2.41

/year,

P .05

(- 1.56

/year)

(- 3.71

/year,

P .01

Chemotherapy

Clinical Experience

Standard RiskChildren

PNET 4

Surgery Randomisation

start RT < J 40

Chemo

CCNU, Cisplatin,

Vincristine

8 Cycles

HF RT1.0 Gy x 2

36/60/68/36 Gy

+ Vcr

St RT

1.8 Gy x 1

23.4/54/23.4 Gy

+ Vcr

PNET 4

n Deaths

340 47

67 events: 66 relapses 1 death CCR

First relapse + 2 months Latest relapse at + 5.5 year

7 Year EFS 0.79± 0.04 (HFRT)7 Year EFS 0.76± 0.04 (Standard RT)

p=0.82

7 Year OS 0.82±0.03

NEXT STEPLow

risk

Standard

risk

High

risk

Large Cell/

Anapastic - - +

Residue/

Metastasis< 1.5 cm2 < 1.5 cm2 > 1.5 cm2

MYC - - +

β-catenin (WNT) + - +/-

StrategyDecrease

treatment

(except if >16)

Standard

treatmentIncrease

treatment

Clinical Experience

Standard riskAdults

Bologna 1989 to 2009 95 pts

36Gy + 18 Gy to tumor bedRT

ANOCEF 1990 and November 2001, 46 pts

STANDARD RISK ADULTS

Courtesy Alba Brandes

Courtesy Luc Talliandier

5y PFS 10y EFS

52% 46%

SCHÉMA DE TRAITEMENT

2 courses chemo

(Carbo AUC 5 D1

etoposide 100 mg/m2 d 1-3)

PROSPECTIVE ANOCEF RSMA

PI: Luc Taillandier

CT RT CT

Radiotherapy before day 80

24 Gy axis + 54 Gy tumor bed

2 courses of chemotherapy

2/3 dose

Clinical ExperienceHigh RiskChildren

High dose chemo: PNET HR +5

B

I

O

P

S

I

E

+/-

E

X

E

R

E

S

E

VP

CBP

HDThiotepa

HDThiotepa

E

X

E

R

E

S

E

R

A

D

I

O

T

H

E

R

A

P

Y

36Gy

CSP

VP

CBP

CSP

Cytapheresis

E

X

E

R

E

S

E

IRM IRMIRM

2 cyclesTMZ

2 cyclesTMZ

2 cyclesTMZ

IRM IRM IRM

64 patients (MB=51; sPNET=13) from 2009 to 2012, 3 year Follow-up

3-year PFS 80%, 3-year OS 85%

Dufour, SFCE

Tarbell JCO 2013

INCREASING DOSE OF CSI

Clinical ExperienceHigh Risk

Adults

Bologna 1989 to 2009 95 pts

ANOCEF 1990 and November 2001, 46 pts

Courtesy Alba Brandes

Courtesy Luc Talliandier

CT RT CT

High RISK ADULTS

DEC Cisplatin 80 to 100 mg/m2-

Etoposide 100 to 200 mg/m2

Cyclophosphamide 600 to 1000 mg/m2

Or CBDCA AUC 5

Etoposide 300 mg/m2

Or MOPP

5y EFS 10y EFS

50% 36%

36Gy + 18 Gy to tumor bed

Beware ofTOXICITY

FEASIBILITY/TOXICITYCDDP/Lomustine/VCR

95 courses

Children

(5-10)

142 courses

Adolescents

(10-20)

p

Dose

Reduction24% 56% 0.02

Delayed

Chemo3% 23% 0.0003

Tabori Cancer, 2005, 1874

Beier JNO 2018

Adaptations required

IQ loss due to supra tentorial RT

>7

Year

<7

Year

Mulhern J Clin Oncol 2OO5, 23:5511-5519.

CSI 23 Gy CSI 36-39 Gy

(- 0.42

/year)

(- 2.41

/year,

P .05

(- 1.56

/year)

(- 3.71

/year,

P .01

Fig 1 Modification of professional status according to the (from treatment) and CSA doses.

Loss of employment

SUNYACH Communication personnelle

< 30,6Gy

> 30,6Gy

Delayed endocrinological toxicity in pediatric population

ACTH deficiency : 38+/-6%

TSH deficiency : 23+/-8% (11% if <42 Gy vs 44% if> 42 Gy: p

0.014)

GH Deficiency: 93+/-4%

Primary Thyroid deficiency : 65+/-7% (54% if <42 Gy vs 89% if> 42 Gy: p

0.017)

Laughton, JCO 2008, 1112

Hypothyroidism

Children Adults

Central TSH deficiency 0% 26%

Peripheral SCH 43% 0%

Second malignancies?.

Broniscer Cancer 2004

Relapses

Smoll (SEER) cancer 2011

Long term differs?

Anti SHH:

One impressive response in adult medulloblastoma

Converging?

R

Modified NOA-07* (see page 2)

SHH M0 (p53wt) (postpub.)

Modified NOA-07 ,with radiotherapy* dose reduction (CSI 23,4 Gy)

and LDE225 200 mg OD daily or with drug holidays

Stan

dar

d

arm

Exp

eri

me

nta

l ar

m

WNT M0 (18+)Modified NOA-07 ,with radiotherapy* dose reduction (CSI 23,4 Gy)

n=90

n=90

15%

60%

15% n=24

n=13

Group 4 M0 (18+)

Modified NOA-07 ,with radiotherapy* dose reduction (CSI 23,4 Gy)

WNT M0 (18+)SHH M0 (p53wt) (postpub.)Group 4 M0 (18+)

Inte

rme

dia

te-r

isk

pat

ien

ts

GLIOMAS

ADULT HIGH GRADE GLIOMAS

Though different…..

HERBY

BEV, bevacizumab; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; RT, radiotherapy; TMZ, temozolomide

Pediatric High grade gliomas

EFS rates (central review; secondary endpoints)

RT/TMZ (n=59) BEV + RT/TMZ (n=62)

6-month EFS rate (95% CI) 66% (53–77) 68% (55–79)

1-year EFS rate (95% CI) 48% (35–61) 38% (26–51)

8.2 months(95% CI 7.8–12.7)

11.8 months(95% CI 7.9–16.4)

Stratified HR 1.44 (95% CI 0.90–2.30) p=0.13 (log-rank test)

BEV + RT/TMZ (n=62)RT/TMZ (n=59)

Time (months)

0

100

0 6 12 18 24 30 36 42

20

40

60

80

Pro

ba

bilit

y o

f E

FS

(%

)

48

RT/TMZ

BEV + RT/TMZ

No. at risk

59 37 26 16 9 6 2 242 32 21 14 7 4 2 2

62 40 20 12 7 5 1 153 29 18 8 6 2 1 1

BRAIN STEM GLIOMAS

DIPG biopsies

Roujeau T, Machado G, Garnett MR, et al. Stereotactic biopsy of

diffuse pontine lesions in children. J Neurosurg. 2007

DIPG biology

EGFR (amp): 40% DIPG

mTO

R

erlotinib dasatinib

everolimus

MET inhibitor, crizotinib

nimotuzumab

PTEN loss: 60% DIPG

GERM CELL TUMORS

Pineal+/- supra sellar

GERMINOMAS

Calaminus Neurooncol 2013

EFS Pts Prot. Germinomas

0 12 24 36 48 60 72 84mois

0

0,2

0,4

0,6

0,8

1p

option A (CSI)

option B (CT+focal)

0.85±0.06

0.93±0.04

(CR 109/113)

(CR 45/51)

p=0.03

**

*

Cumulative Recruitement

Age French patients GCTII

0

2

4

6

8

10

12

14

<14 14-18 19-25 >26

Converging?

WEB CONFERENCE AYAEach Monday….

2016185 presentations

0

20

40

60

80

100

120

MEDULLO ET PNET GLIOMES TGM EPENDYMOMES PINEALE NF1 MOELLE TRONCS

185 presentations of 145 patients

0

10

20

30

40

50

60

70

1ere intention 2 ieme intention 1ere=> puis à la rechute

1 fois

2fois

3fois

4fois

1rst Line 2nd Line 1rst => Further Line

once

Twice

Three T

Four T

Ages

0

2

4

6

8

10

12

14

20-30 Yr 30-40 Yr > 40 Yr

Age of patientsaccording to type of tumor

Mean Median Younguest Oldest

Medulloblastoma 31 29 16 64

Germ cell Tumor 23 22 7 47

Ependymoma 35 30 4 75

Pineal 43 19 18 87

PNET 37 29 17 73

Low grade Glioma 30 26 17 55

High Grade Glioma 27 22 15 60

Else 30 24 9 57

Inot documented 34 29 10 62

SPECIALISTS

0

2

4

6

8

10

12

14

16 CHIR

ONCO

PED

ANAPATH

NEURO ONCO

ONCO

RT

CONCLUSIONS

Inclusion ages

Fern 2014 Lancet Oncol

TGM SIOP GCTII (any age)

BIOMEDE (- months-25 Year)

PersoMed (Pubertal Bone age-…….

A multidiciplinary team

• A Pathologist up to date• A Molecular biologist • A surgeon used to « travel » in the PF• A radiotherapist used to CSI• An oncologists used to toxicities• An endocrinologist• A Quos specialist• A neurologist• Pediatric with adult multidisciplinary discussion

? Dedicated Units???Long term Follow-up of chronic sequelae..