Transmembrane Signal transduction

1
Spindle cell sarcomas Rational choice of when to
use chemotherapy

• JY Blay
• Unité doncologie Médicale, Hôpital Edouard
  Herriot
• Unité Inserm 590, Centre Léon Bérard
• EORTC Soft Tissue and Bone Sarcoma Group
• CONTICANET Network of Excellence

2
Chemotherapy

• Adjuvant
• Neoadjuvant
• Advanced phase 1st line
• Advanced phase gt1st line

3
Adjuvant chemotherapy (2008 ESMO)

• No consensus
• Not a standard option
•  No treatment arm  still a standard
• May be discussed in multidisciplinary setting
• which objective?
• Which patients (Size, grade, histotypes ...)
• Targeted treatment to be explored?
• New meta-analysis needed

Casali PG, Jost L, Sleijfer S, Verweij J, Blay
JY ESMO Guidelines Working Group. Soft tissue
sarcomas ESMO clinical recommendations for
diagnosis, treatment and follow-up. Ann Oncol.
2008 May19 Suppl 2ii89-93
4
ADJUVANT CT in STSMETA-ANALYSIS
Lancet, 1997 13 trials 1502 patients
Metastases at 5 years 50 Five-year survival
60
Rec Loc p 0.024 HR 0.74 (0.57-0.96)
5 à 5 ans
Mets p 0.0003 HR 0.69 (0.57-0.84)
9 à 5 ans
SSR p 0.00008 HR 0.74 (0.63-0.86)
10 à 5 ans
SG p 0.087 HR 0.87 (0.75-1.02)
4 à 5 ans
- Adjuvant CT not a standard in 2007 - Should
include anthracyclins
5
1568 patients in 14 randomised trials comparing
chemo with no chemo
Meta-analysis of adjuvant chemotherapyfor soft
tissue sarcoma
Chemo
SMAC 1997, Lancet 3501647-54
6
1568 patients in 14 randomised trials comparing
chemo with no chemo
Meta-analysis of adjuvant chemotherapyfor soft
tissue sarcoma
Chemo
No chemo
4 benefit Treat 100 patients for 4 lifes
saved?
SMAC 1997, Lancet 3501647-54
7
ISG randomized adjuvant extremity sarcoma study

• 104 patients randomized to surgery and radiation
  alone, or the same with epirubicin ifosfamide
  chemotherapy
• Primary endpoint improved DFS (not OS)
• Study stopped before 180 patient accrual due to
  meeting its DFS endpoint (plt0.001)
• Median DFS
• Chemo 48 months
• Control 16 months

Frustaci et al. JCO 2001 191238
8
Adjuvant therapy ISG trial
OS
DFS
Frustaci et al. JCO 2001 191238
9
EORTC 62931 - Study design
Randomised trial of postoperative chemo vs
nonedoxorubicin 75mg/m2 ifosfamide 5g/m2
lenograstim q 3wk x 5
Powered to detect 5yS 50 ? 65
Biopsy or inadequate surgery
No adjuvant chemotherapy
R A N D O M I S E D

• RADIOTHERAPY ASSESSMENT
• RT indicated for
• microscopic
• residual disease
• inadequate margins
• local recurrence

Definitive surgery
RT if indicated
Adjuvant chemotherapy
Maximum 4 weeks
10
EORTC 62931 - Chemotherapy

• Doxorubicin 75mg/m2
• Ifosfamide 5g/m2
• Lenograstim 3µg/kg sc daily x 14
• 5 cycles
• Repeated every 3 weeks

Dose insufficient?
11
EORTC 62931 - Relapse free survival
5 year RFS Observation 53 95 CI 46,
61 Chemotherapy 51 95 CI 43, 59
No difference in local or distant RFS
12
EORTC 62931 - Overall survival
Excludes HR of 0.62
13
Control arm improved between 62771 and 62931
14
New meta-analysis (SMAC 2007) on published data
A new meta-analysis on source data is needed!
SMAC 2007, CTOS 2007
15
Adjuvant CT future

• A randomized trial in selected groups
• Selected regimen according to molecular type
• Anti- angiogenics targeted agents

16
1. A randomized trial in selected
groups(unfavorable groups selected on subgroup
analysis)

• ASCO 2008 (A. Le Cesne al) meta-analysis of
  the 2 randomized EORTC adjuvant trials
• N819 patients
• Which are the predictive factors for benefit of
  adjuvant treatment (OS/PFS)?
• Young (lt40) age NO
• Synovials NO
• Uterine LMS NO
• Patients benefiting for adjuvant treatment
• PFS gt40, males, R1, non synovials (?)

17
2- Pharmacogenomics (e.g. ET-743)
Tetrahydroisoquinoline alkaloid
Ecteinascidia turbinata
EMEA recommendation for approval 19th July
2007 "Yondelis is indicated for the treatment
of patients with ASTS, after failure of
anthracyclines and ifosfamide or who are
unsuitable to receive these agents. Efficacy
data are based mainly on liposarcoma and
leiomyosarcoma patients"
18
2. Personalised adjuvant treatment in
STS?TC-NER / outcome of pts treated with
trabectedin
P. Schöffski et al. AACR 2007
19
Adjuvant Yondelis - Study design
Randomised trial of postoperative chemo vs
nonetrabectedin 1500µg/m2- 24hCI 3wk x 6
Powered to detect 2yPFS 50 ? 75
Biopsy or inadequate surgery
No adjuvant chemotherapy
R A N D O M I S E D

• RADIOTHERAPY ASSESSMENT
• RT indicated for
• microscopic
• residual disease
• inadequate margins
• local recurrence

Definitive surgery
RT if indicated
Adjuvant chemotherapy
Low BRCA1/high ERCC1
Max 6? weeks
20
3. Randomizing targeted treatments

• Selected subtypes?
• Pre-screen with short neoadjuvant course?
• DC-MRI
• Contrast enhanced US
• CT scan
• PET

21
Chemotherapy

• Adjuvant
• Neoadjuvant
• Advanced phase 1st line
• Advanced phase gt1st line

22
Neoadjuvant chemotherapy (ESMO 2008)

• Not a standard option
• May enable to induce tumor shrinkage
• For limb-sparing surgery
• For macroscopically complete surgical removal
• Multidisciplinary decision

Casali PG, Jost L, Sleijfer S, Verweij J, Blay
JY ESMO Guidelines Working Group. Soft tissue
sarcomas ESMO clinical recommendations for
diagnosis, treatment and follow-up. Ann Oncol.
2008 May19 Suppl 2ii89-93
23
Gortzak E, et al. A randomised phase II study on
neo-adjuvant chemotherapy for 'high-risk' adult
soft-tissue sarcoma. Eur J Cancer. 2001
Jun37(9)1096-103.

• 134 patients
• Randomisation
• 3 courses of CT surgery
• Surgery alone
• Limb-salvage was achieved in 88, amputation was
  necessary in 12
• (all according to the plan at randomisation).
• At a median follow-up of 7.3 years
• 5 year disease-free survival is 52 for the no
  chemotherapy and 56 for the chemotherapy arm
  (P0.3548).
• 5 year overall survival for both arms is 64 and
  65, respectively (standard error 7) (P0.2204).

24
62871 randomized clinical trial testing
neodjuvant CT in operable patients
Limb-salvage was achieved in 88, amputation was
necessary in 12 (all according to the plan at
randomisation).
25
ESHO/EORTC 62961 Study design
S1 primary tumor 5 cm, GII/GIII S2 local
recurrence of S1 tumor S3 inadequate surgery
of S1 or S2 tumor
Risk groups
R
R
A
RHT
A
RHT
Arm A
Arm A
D
D
EIA
EIA
I
I
R
R
A
A
T
T
I
I
EIA
EIA
Arm B
Arm B
O
O
N
N
Stratification Center, Risk Group, Extremity,
Non-Extremity
26
Disease Free Survival
Cox hazard ratio0.65 CI950.49-0.87, p0.003
27
Metastatic phase
28
Chemotherapy

• Adjuvant
• Neoadjuvant
• Advanced phase 1st line
• Advanced phase gt1st line

29
2 (1) active agents?

• Doxorubicin RR 9-25
• Ifosfamide RR6-100
• DTIC? RR 10-20 (?)

30
Soft Tissue Sarcomas Treatment Algorithm
LOCAL DISEASE
Surgery Radiotherapy
CURE (40-50)
METASTASES (50-60)
Surgery (10)
1st line Doxorubicin Ifosfamide
Combination OS 10-12 mo
2nd line Ifosfamide Doxorubicin
? PFS short
3rd line ? ?
?
31
EORTC STBSG 62971Dox vs Ifo 3x3 vs Ifo 3x3ci
Toxicity IfogtgtDoxo
32
ASTS poly CT vs mono CT
Authors regimen N RR Survival Schoenfeld A/AVC
/AdVC 200 A 27 (p 0.03) NS Muss A/AC 104 NS
NS Omura A/AD 146 NS NS Borden A/AD 186 AD
30 (p 0.02) NS Lerner A/AD 66 AD 44
(leiomyo S) NS Santoro A/AI/CYVADIC 449 NS NS B
orden A/AVd 295 NS NS Edmonson A/AI/APM 262 AI
34 (p 0.03) NS Antman AD/MAID 340 MAID 32
(p 0.002) NS
33
Phase II trials in STSFirst line chemotherapy
OR PD
Single agent Poly CT Doxorubicine
8-30 AI, MAID Ifosfamide 6-45 30-50
34
Soft Tissue Sarcomas advanced phase
Median Survival 10-12 months
Results from the only 8 randomized trials in 1st
line treatment with more than 100 patients each,
including a total of 1922 patients, show
Combinations more toxic No impact on
survival Impact on response
35
PROTOCOL 62012 Randomized trial of single agent
doxorubicin versus doxorubicin plus ifosfamide
Study Coordinator I. Judson, London

• Eligibility
• High grade STS (2-3)
• Age 16-60
• No previous chemo for adv/met dis
• WHO PS lt 2

• Stratification
• Age (lt50 vs 50)
• PS (0 vs 1)
• Liver mets (0 vs )
• Histological grade (2 vs 3)

36
Long term survival in advanced STS
37
Long term survivors

• Table 2 Response to first line
  doxorubicin-containing regimens.
• __________________________________________________
  _________________________
• Response to 5-year Others p of 5-year
• 1st line survivor survivors among
• (n66) (n1822) response subgroup
• N () N ()
• CR 17 (31) 64 (4) 17/81 (21)
• PR 17 (31) 306 (19) 17/323 (5)
• SD 17 (31) 641 (39) 17/658 (3)
• PD 3 (6) 627 (38) 0.00001 3/630 (0.5)
• __________________________________________________
  _________________________
• patients with a minimum follow-up of 5 years
  after inclusion who died within the 5 years of
  inclusion.
• Response was not documented in 196 (10)
  patients

EJC 2002
38
STUDY 62933 DESIGNStudy coordinator A. van
Geel, Rotterdam
39
Connective tissue tumours5 types of sarcomas

• Associated with specific translocations
  generating fusion genes
• Ewing t(1122)
• Synovialosarcomas t(X18)
• Alveolar rhabdomyosarcomas t(113), t(213)
• DSRCT t(1122)
• etc...
• Kinase mutations (KIT, PDGFR in GIST)
• Gene inactivation (INI in rhabdoid tumors, NF1 in
  MPNST )
• Simple genetic alterations amplifications
  (mdm2cdk4 in LPS)
• Complex genetic alterations (MFH, LMS, ...)

40
Molecular biology

• Clinical
• research

41
DFSP
Targeting a mutated kinase /ligand

• DFSP /giant cell fibroblastoma
• t(17,22) 17q22 and 22q13 (COL1A1 et PDGFB)
• Autocrine loop with PDGFb

Maki et al IJC, Rubin et al JCO Mc Arthur et al
JCO
42
PVNS/TGCT
2.Targeting a mutated kinase /ligand

• Giant cell tumor of the soft part
• t(1,2) (COL6A3 et CSF1)
• Autocrine/paracrine loop with CSF1

43
Liposarcomas

• Gene Response to
• alteration ET-743
• WDLPS and DDLPS mdm2/cdk4 1040SD
• Myxoid LPS t(12,16), t(12, 22) gt50
• Pleomorphic LPS complex ?
• F. Grosso et al

44
Find a target using expression microarrays ?
(Nielsen Lancet 2002)

• Synovial sarcoma
• t(X,18)
• Over expression of HER1
• gefitinib single agent
• Clinical trial
• 62022 EORTC STBSG
• Single agent in HER1 SynS
• Patients with advanced disease failing AI
• N47- Completed sept 05
• ASCO 2006

HER1
KIT
45
(No Transcript)
46
Specific subtypes may be more sensitive to
specific agents

• Subtype Drug
• Synovial Sarcoma Ifosfamide (go to ASCO 2008)
• Angiosarcoma (scalp) Paclitaxel
• Angiosarcomas Sorafenib
• Leiomyosarcoma (general) ET-743
• Leiomyosarcoma (uterus) Dacarbazine
• Leiomyosarcoma Gemcitabine Docetaxel
• Liposarcomas ET-743
• Aggressive fibromatosis Imatinib ?
• MRCL (fusion protein?) ET-743
• DFSP (PDGF) Imatinib
• ESS low grade ER (ER) aromatase inhibitors
• PVNS (CSF1) imatinib
• Bone GCT (RANKL) Denosumab

47
Rational choice of when to use chemotherapy
KIT PDGFR ?
del 14q
KIT PDGFR ?
del 22q
del 1p
8q
5p
75
38
33
29
44
90
All GIST
GIST high risk
Metastatic GIST
when we have identified the  initial 
 master  biological event
48
Active agents

• 2000 Doxorubicin, ifosfamide, /-DTIC
• 2007 Doxorubicin, ifosfamide, gemcitabinedocetax
  el, paclitaxel, trabectedin, brostallicin,
  imatinib, sunitinib, AP23573, DTIC

49
Conclusions

• Adjuvant CT still experimental
• Neoadjuvant CT reduce tumor size to enable
  surgery
• Metastatic setting
• 8 curative
• Not only doxo a/o ifosfamide
• CT histotype-specific
• Targeted oncogene treatment

50
Molecular biology

• Clinical
• research

51
Thanks tothe patients who participated to the
clinical trials