sarcomi delle parti molli - aieop.org · ferrari andrea milano int x gasparini patrizia milano int...

Sarcomi delle parti molli

nome centro firma Alaggio Rita Padova x Basso Eleonora Torino x Bertolini Patrizia Parma x Bisogno Gianni Padova x Burnelli Roberta Ferrara apologies Casanova Michela Milano INT apologies

Cecinati Valerio Pescara x

Chiaravalli Stefano Milano INT x Collini Paola Milano INT apologies Coccoli Luca Pisa x D’Angelo Paolo Palermo x De Bortoli Verona x

Di Cataldo Catania x Ferrari Andrea Milano INT x Gasparini Patrizia Milano INT x Giurici Nagua Trieste x Indolfi Paolo Napoli Univ II x Lobello Cosenza x Mazzitti Carla Genova no Meli Claudia Catania x Miglionico Lucia S.Giovanni Rotondo x

Milano Giuseppe Roma OPBG x Nonnis Antonella Cagliari apologies Perruccio Katia Perugia x Quaglietta Lucia Napoli Pausillipon x Ruggiero Antonio Roma Gemelli x Scarzello Giovanni Padova x Tamburini Angela Firenze x Zin Angelica Padova x Angela Scagnellato Padova x Ilaria Zanetti Padova x Simona Affinita Padova x Barbara Diletto Milano INT x Lorenza Gandola Milano INT x Cano Carmen Modena x Fraia Melchionda Bologna x Giuseppe Scimone Salerno x Daniela Di Pinto Napoli Univ II x Galea Eulalia Catanzaro x Pietro Lapidari Milano INT x Abate Massimo Bologna IOR apologies

De Leonardis Francesco Bari apologies

Maurizio Mascarin Aviano apologies

38 persone da 24 centri!!!

0 10 20 30 40 50 60 70 80 90

100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300

INTMI

PADOVA

ROMA B.G.

GENOVA

NAPOLI PAUSILLIPON

TORINO

FIRENZE

NAPOLI II ATENEO

PALERMO

PISA

CATANIA

ANCONA

ROMA GEMELLI

RMS

NRSTS

intermediate

missing

EpSSG RDE System – Italian registered at 07.10.2015 – total 985

0 10 20 30 40 50 60 70 80 90

100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300


Event Free Survival Overall Survival

N Events

EFS

Events

OS

3-yr

(95% CI)

p-value 3-yr

(95% CI)

p-value

Center 0.8581 0.9597

≤ 40 patients enrolled 100 25 14 77.1 (66.6-84.6) 89.3 (80.3-94.3)

> 40 patients enrolled* 199 47 24 75.1 (67.5-81.2) 86.8 (80.4-91.3)

Univariate analyses by Center according number of patients enrolled * INTMI, Padova, Roma BG, Genova.

0 10 20 30 40 50 60 70 80 90

100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300


Event Free Survival Overall Survival

N Events

EFS

Events

OS

3-yr

(95% CI)

p-value 3-yr

(95% CI)

p-value

Center 0.8581 0.9597

≤ 40 patients enrolled 100 25 14 77.1 (66.6-84.6) 89.3 (80.3-94.3)

> 40 patients enrolled* 199 47 24 75.1 (67.5-81.2) 86.8 (80.4-91.3)

Univariate analyses by Center according number of patients enrolled

0.4394 0.7120

Milano-Padova 166 41 21 73.6 (65.0-80.5) 86.1 (78.7-91.1)

Other centres 133 31 17 78.4 (69.6-84.9) 89.4 (82.1-93.9)

0-14 years old observed expected O/E ratio

RMS 1139 1488 0.77

NRSTS 615 1234 0.50

all STS 1754 2722 0.64

15-19 years old observed expected O/E ratio

RMS 201 315 0.64

NRSTS 163 902 0.18

all STS 364 1217 0.30

Access to clinical trials for adolescents with soft tissue sarcomas: enrolment in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols A Ferrari, A Trama, A De Paoli, C Bergeron, JHM Merks, M Jenney, D Orbach, J Chisholm, S Gallego, H Glosli, GL De Salvo, L Botta, G Gatta, G Bisogno, and RARECAREnet Working Group Ped Blood Cancer, in press

compiti e ruoli dei membri del GdL

compiti e ruoli dei membri del GdL

dati partecipazione ai meeting EpSSG analisi/pubblicazioni … …

GdL AIEOP 1. Eleonora Basso – Torino 2. Patrizia Bertolini – Parma 3. Paolo D’Angelo – Palermo 4. Gianni Bisogno – Padova 5. Paolo Indolfi – Napoli Un II 6. Carla Mazzitti – Genova 7. Giuseppe Maria Milano – Roma OPBG 8. Angela Tamburini – Firenze + consulenti

Pubblicazioni su casistica AIEOP-STS

39 papers dal 2000 ad oggi primo autore: 19 padova, 19 milano, 1 palermo autori da 23 centri differenti

padova 39 (con 24 autori diversi) milano 38 (con 10 autori) genova 16 (con 6 autori) roma OPBG 13 (7 autori) napoli 10 (2) palermo 7 (4) torino 5 (2) catania 4 (1) bergamo 3 (2) trieste 3 (1) bologna 3 (3) ancona 3 (2) bari 2 (2) cagliari 2 (2) pisa 1 (1) aviano 1 (1) brescia 1 (1) perugia 1 (1) roma gemelli 1 (1) roma sapienza 1 (1) ferrara 1 (1) novara 1 (1) san giovanni rotondo 1 (1) 0

5

10

15

20

25

30

35

40

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

5

2000 1

2001 3

2002 4

2003 3

2004 3

2005 5

2006 3

2007 2

2008 4

2009 2

2010 3

2011 1

2012 3

2013 0

2014 0

2015 0

39 papers dal 2000 ad oggi


39 papers dal 2000 ad oggi


NRSTS viscerali DSRCT MPNST recidivati RMN N1 RMS vagina RMS vie biliari

The loveliest soft tissue sarcomas experts in the world


EpSSG Chairmen

Joern Treuner, Modesto Carli,

Odile Oberlin, Michael Stevens

RMS TMC chair

Gianni Bisogno

NRSTS TMC chair

Andrea Ferrari

Radiotherapy Panel Chair

Andreas Schuck/Mark Gaze

Surgical Panel Chair

Helene Martelli

Pathology Panel Chair

Anna Kelsey

Biology Panel Chair

Angelo Rosolen

Radiology Panel Chair

Kieran McHugh

Early phase Committee Chair

Julia Chisholm

Statistical & Data Management Panel Chair

Gian Luca De Salvo

EpSSG Chairmen

Gianni Bisogno

RMS TMC chair

Gianni Bisogno/M Jenney,

NRSTS TMC chair

Andrea Ferrari

Radiotherapy Panel Chair

Henry Mendeville

Surgical Panel Chair

Helene Martelli

Pathology Panel Chair

Anna Kelsey

Biology Panel Chair

Janet Shipley

Radiology Panel Chair

Kieran McHugh

Early phase Committee Chair

Michela Casanova

Statistical & Data Management Panel Chair

Gian Luca De Salvo/Keith Wheatley


Protocol Activation

date

Status Enrolled cases

EpSSG RMS 2005

prospective randomized trial on localized RMS 31.03.2005 ongoing 1656

EpSSG NRSTS 2005

prospective observational study on localized NRSTS 31.03.2005 ongoing 971

EpSSG MTS 2008

prospective observational study on metastatic RMS/NRSTS 22.09.2008 ongoing 326

EpSSG/ITCC/Roche Bernie

prospective randomized trial on metastatic RMS/NRSTS 01.07.2008 31.10.2013 154

EpSSG clinical protocols for newly diagnosed patients

15 countries, 131 centers

Localized RMS

Localized NRSTS

Metastatic STS


rhabdomyosarcoma

RISK

GROUP

HIST IRS N SITE SIZE

& AGE

% EFS-OS

A fav I N0 any fav 6% 90-95%

B fav I N0 any unfav

6% 78% - 90%

C fav II-III N0 fav any

18% 72% - 88%

D fav II-III N0 unfav fav 9% 80% - 85%

E fav II-III N0 unfav unfav 27% 55% - 60%

F fav II-III N1 any any

8% 50% - 60%

G unfav I-II-III N0 any any

20% 50% - 60%

H unfav I-II-III N0 any any

6% 40% - 50%

EpSSG RMS 2005

VA

IVA+VA or IVA ± RXT

IVADo + RXT + VNR-oral CTX

1° random 2° random

IVA + RXT

IVADo + RXT

stop-therapy

maintenance VNR-oral CTX

RMS 2005 – a protocol for localised RMS

R

IVA

IVADo

R

stop therapy

R

IVA

IVADo

Doxorubin does not add

any significant

“anti RMS activity”

to a standard multidrug

regimen ?

R

stop therapy

R

stop therapy

2nd Randomisation

Study closure 12/2016

(IV Amendment: Go on to randomize a total

of at least 370 patients to the maintenance

question)

Performance Italiana in RMS2005

IVADo e Mantenimento sono strategie “italiane” Buon numero di pazienti randomizzati Abbiamo dati migliori ? (90% dei pz randomizzati sono validati) Importante funzione di coordinamento e data managing (52.108 schede)

30/33 Centri attivi: pazienti eligibili ma non randomizzati o trattati senza prot. approvato da C.E. (richieste tardive)

Problemi nella raccolta dati: • Ritardo registrazione pazienti non randomizzati • Difficoltà nell’ottenere copia dei referti radiologici, chirurgici • Ritardo nell’inserimento dati (e quindi pazienti non randomizzati per il mantenimento)

SAE non registrati

Problemi nella - revisione della diagnosi - nella centralizzazione del materiale biologico

Gianni Bisogno, Riccione 2015

STAR

T OF LO

CA

L THER

AP

Y

RESP

ON

SE ASSESSM

ENT

D

ecision

on

local th

erapy

Rad

ioth

erapy ran

do

misatio

n

(see R

T schem

a)

C5 C6 C7 C8 C9 C1 C2 C3 C4 SR

C5 C6 C7 C8 C9

C5 C6 C7 C8 C9

C5 C6 C7 C8 C9

C1 C2 C3

C1 C2 C3

C1 C2 C3

C4

C4

C4

IVA

IRIVA

IVA+

HR CT2B

Maintenance 6 cycles


C4 C5 C6

C4 C5 C6

C4 C5 C6

C1 C2 C3

C1 C2 C3

C1 C2 C3

C8 C9

C8 C9

C8 C9

C7

C7

C7

IVADo

IRIVA

IVA+

INDUCTION CHEMOTHERAPY

CHEMOTHERAPY RANDOMISATION 1

CT1

DISEA

SE ASSESSM

ENT

STAR

T OF LO

CA

L THER

AP

Y

VHR CT2A


CHEMOTHERAPY RANDOMISATION 2

CT2


RESP

ON

SE ASSESSM

ENT

RESP

ON

SE ASSESSM

ENT

D

ecision

on

local th

erapy

Rad

ioth

erapy ran

do

misatio

n

(see R

T schem

a)

END

CT1A

CT1B

Intervention: Frontline Randomisations

FaR-RMS Trial Schema

• Overarching flexible design

– Allows new agents to be assessed up front and at relapse – Several questions can be asked for an individual patient not just

frontline chemotherapy – When new interesting drugs become available, trial structure

and design allow efficient introduction of new arms to the study (without the need to build a complete new study each time)

FaR-RMS

– MAMS (multiarm multistage) design (ineffective arms being dropped)

– Frontline chemotherapy in localized and metastatic patients

– Relapse RMS

– Phase Ib in VHR patients only, e.g. to determine the dose of Irinotecan (Ir) to be

used in combination with standard doses of IVA (IrIVA)

– Phase II/III induction systemic therapy randomisation (to determine whether new therapeutic strategies are associated with improved survival; e.g. compared to IVADo for VHR, compared to IVA for HR RMS)

– New drugs

– Maintenance chemotherapy, e.g. VHR (12 vs 24 cycles) and HR (6 vs 12)

– Radiotherapy (randomised phase II, feasibility)

– Radiology (PET)

– Biology

FaR-RMS

Probably Supported National Support ? Low Performance in RMS2005 Future EpSSG partner ? CWS

‘FaR-RMS’ Timelines

Dec 2015: CRUK

Outline app.

Submitted

Mar/Apr 2016:

Outcome of outline

app.

Mid Apr

2016: CRUK Full app.

opens

01 May 16:

Finalised schedule of events & patient pathway

for full UK costing

20 Jun 16: CRUK Full

app. submission deadline

Dec 2016:

Outcome of full app.

Dec16/ Jan17: Other

countries apply for funding

Autumn 2017: UK Ethics & CA app.

submitted

Open trial in UK by Dec

2017

Open other

countries by

Mid/End 2018

Problemi:

Studio estremamente complesso

Biologia molecolare per tutti i pazienti (entro 3 settimane)

PET alla diagnosi e alla rivalutazione (studio randomizzato RT su ruolo PET)

Decisione sulla “resectability “ del tumore

Revisione centralizzata del piano di RT prima di iniziare la RT mettendo online i piani di trattamento (sistema VODKA)

Studio di fase Ib (IrIVA, new drugs: solo i Centri ITCC ?

Protocollo recidive (new drugs): quanti Centri ?

Risorse (assicurazione, monitoraggio, invio campioni, …)(dipendono anche dal numero di pazienti e di Centri)

FaR-RMS


NonRhabdomyosarcomaSoftTissueSarcoma

NRSTS 2005 PROTOCOL

Synovial sarcoma

“Adult-type” STS

Other histotypes

prospective non-randomized historically-controlled trials

guidelines

“first objective of the study is to make uniform the treatment of NRSTS

patients in Europe”

NonRhabdomyosarcomaSoftTissueSarcoma

Study closure 12/2016

NRSTS 2017 prospective cohort study with a biological question

or

“bio-registry”

Treatment guidelines SS IFS AF ASPS Adult-type … …

Genomic instability? Liquid biopsy? … … ??? Clinical trial

Clinical trial

Clinical trial

EURO RHABDOID 2017 Desmoid-type

fibromatosis project

COG other cooperative groups CWS Adult groups


guidelines

High risk group Non resected tumor

ID

I-D

I-D

I-D

I-Paz

I-Paz

I-Paz

Local MRI Chest X Ray

Best local therapy

Paz 6 months

Randomization

Stop therapy

If absence of progression After 3 cycles

High risk group Non resected tumor

ID

I-D

I-D

I-D

I-Rego

I-Rego

I-Rego

Local MRI Chest X Ray

Best local therapy

Rego 6 months

Randomization

Stop therapy

If absence of progression After 3 cycles

A new randomised study An international sponsor A lot of national sponsors An insurance …money… A new database or new CRFs …money… New rules: monitoring, pharmacovigilance …money…

Number Cooperation/partner

A new drug for a scientific question

Time (years)

EpSSG 2016

Refractory disease

RMS 2005/ FaR-RMS

Local treatment if possible

Phase 1b ESMART

CRIPS

Personalised treatment VI + Regorafenib

FaR-RMS phase 1b

Phase 2 : VI+/-T and FaR-RMS

Phase 2: Abraxane

Localised disease Metastatic disease

EpSSG MTS2008/FaR-RMS

Relapse

Other phase 1 Cobimetinib

Afatinib LDK378

1-2 dicembre 2016 – EpSSG Bruxelles 10-12 maggio 2017 – EpSSG Copenaghen 4-5 dicembre 2017 – EpSSG Lyon

Mercoledì 18 gennaio 2017 - VII° CORSO dedicato ai SARCOMI DELLE PARTI MOLLI, Aula Magna, Palazzina Servizi - Azienda Ospedaliera di Padova Giovedì e Venerdì 19 e 20 gennaio 2017 - Riunione Annuale Gruppi di Lavoro AIEOP, Sala Auditorium Centro Culturale Altinate / San Gaetano (programma in allegato)

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