Dr Javier Martin Broto Oncología Médica

Hospital Son Espases Palma de Mallorca www.cotmes.com

AGENDA

TTº ENFERMEDAD LOCALIZADA SPB

TTº ENFERMEDAD DISEMINADA SPB

J Clin Oncol 2002 20:791-796.

Enneking Classification of Surgical Margins

SURGERY: THE THERAPEUTIC MAINSTAY

DOES IMPROVE RESECTABILITY?

Resectable Unresectable

80% 5%

15%

Resectable ?

Every attempt should be made to avoid positive microscopic surgical margins

CT-RT can maximize downstaging

3 courses CT (E.I.) + RT (50 Gy)

90 mm

3 courses CT (E.I.) + RT (50 Gy)

Cancer 2012;118:5857-66

CHOI CRITERIA RECIST CRITERIA

Predictive biomarker in Localized Disease

J Martin et al. Mol Cancer Ther 2014, 13 249-259

A preop Tx

• Unlikely converts to resectability 5% of primary STS of extremities

• Improves quality of margins in borderline resectable tumors

DOES IMPROVE SURVIVAL?

Sarcoma Meta-analysis Collaboration (Lancet, 350:1647-54, 1997)

SUPERV RDOS A 10 AÑOS BENEF ABSOL

Valor p

TRATAM CONTROL

SLE 55% 45% 10% 0.0001

SUPERV RDOS A 10 AÑOS BENEF ABSOL

Valor p

TRATAM CONTROL

SG 54% 50% 4% 0.12

SUPERV BENEFICIO ABSOLUTO

Valor p

EE (n= 886)

SG 7% 0.029

Cancer, 113: 573-581. 2008

RIESGO RELATIVO CON 95% DE IC PARA RL, RD, RG, SG

RECURRENCIA LOCAL

RECURRENCIA DISTANCIA

RECURRENCIA GLOBAL

SUPERVIVENCIA GLOBAL

RR 95%IC RR 95%IC RR 95%IC RR 95%IC

DOXO 0.75 0.56-1.01 0.69 0.56-0.86 0.75 0.56-0.86 0.84 0.68-1.03

DOXO+IFOS 0.66 0.39-1.12 0.61 0.41-0.92 0.61 0.41-0.92 0.56 0.36-0.85

TODOS 0.73 0.56-0.94 0.67 0.56-0.82 0.67 0.56-0.82 0.77 0.64-0.93

5% NNT 25 10% NNT 10 10% NNT 10 6% NNT 17

GRUPO DOSIS PERIODO D.I. (mg/m2/s)

NCI 92 ADR 70 IFOS 4

4 SEM X 5 ADR 17.5 IFOS 1000

EORTC 62931 ADR 75 IFOS 5

3 SEM X 5 ADR 25 IFOS 1667

RTOG 9514 ADR 20 D1-3 IFOS 2,5 D1-3 DTIC 225 D1-3

3SEM X2 +4 ADR 20 IFOS 2500 DTIC 225

ITALIA EPI 60 D1-2 IFOS 1,8 D1-5

3SEM X 5 EPI 40 IFOS 3000

HAZARD RATIO CON 95% DE IC PARA SG

GRADO 2 (N=625) HR (95% IC) P

GRADO 3 (N=627) HR (95% IC) P

EDAD > 51 años 2.1 (1.6-2.8) < 0.0001 1.6 (1.2-2.1) 0.0002

TUMOR > 5 cm 1.8 (1.3-2.5) 0.0003 1.6 (1.2-2.2) 0.003

Local superficial NS 0.6 (0.4-0.9) 0.02

Invasión neurovascular

1.9 (1.3-2.6) 0.0001 1.5 (1.1-2.1) 0.003

QTP adyuvante 0.8 (0.6-1.1) 0.15 0.6 (0.5-0.8) 0.0002

A. Italiano et al. Ann Oncol, 2010

P = 0.03

JCO, 2001, Vol. 19, N° 5

P=0.04 Median F.U.=59 m Minimum F.U.=36 m

Biopsy

CT x 3

RT

CT x 2

SURG

RT SURG

R

CT x 3

RT SURG

RT SURG

J Clin Oncol 30:850-856. 2012

J Clin Oncol 2012 Mar 10;30(8):850-6

months

0 12 24 36 48 60

prob

abilit

y

0.0

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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R ht-CT x 3 Chir + RT

EI x 3 Chir + RT

• High grade, adult-type

• Extremity and trunk wall

• >5 cm and/or local rec

Advantages of Complementary Chemo in High Risk EE/TW S III

3 cycles of full doses Epirrubicin-Ifosfamide

Neoadjuvant could give us more information.

In clinical setting: individualized shared decision-making

To enroll patients in a randomized prospective trial is a good

option.

Study Drug N RR Survival

ECOG Doxorubicin 93 19% 8 mo

Doxorubicin + DTIC 95 13% 8 mo

SWOG Doxorubicin + DTIC 79 32% 9 mo

Doxo + DTIC + cytoxan 95 35% 10.5 mo

ISSG Doxorubicin + DTIC 170 17% 13 mo

MAID 166 32% 12 mo

EORTC Doxorubicin 212 24% 12 mo

Doxorubicin + Ifosfamide 202 27% 12 mo

ECOG Doxorubicin 90 20% 9 mo

Doxorubicin + Ifosfamide 88 34% 12 mo

GEIS Doxorubicin 67 23% 26w/pfs

Doxorubicin + Ifosfamide 65 24% 24w/pfs

PHASE II RANDOMIZED STUDY OF SEQUENTIAL DOSE-DENSE DOXORUBICIN AND IFOSFAMIDE VERSUS S-D DOXORUBICIN IN FIRST-LINE ADVANCED STS

J Clin Oncol. 2009 Apr 10;27(11):1893-8

Autor Ifos A Dtic N %RC %RG

Kirchner 7,5 65 0 14 7 43

Elias 7,5 60 900 97 11 51

Antman 7,5 60 900 23 13 57

Hartlap 7,5 50 0 21 14 57

Loeher 5 60 0 38 8 39

Mansi 5 60 0 22 14 41

Bramwell 5 50 850 40 5 25

Schuete 5 50 0 162 9 34

Santoro 5 50 0 144 6 25

8/10/2009

15/12/2010

BASAL SEMANA 2ª SEMANA 6ª

Therefore, multiagent chemotherapy with doxorubicin plus

ifosfamide may be the treatment of choice, especially when

a tumor response is felt to be able to give an advantage and the

performance status is good.

PROGRESSION FREE SURVIVAL

Pro

babi

lity

of

Pro

gres

sion

Fre

e S

urvi

val

Months

p = 0.005

Arm A: DTIC

Arm B: Gemcitabine + DTIC

[0.39 - 0.856]0.579[2.47 - 5.9]4.2 m.Arm B

Ź10.005

[1.25 - 2.75]2 m.Arm A

CI 95%HRp valueCI 95%PFS median

OVERALL SURVIVAL

Pro

babi

lity

of

Ove

rall

Sur

viva

l

Months

Arm A: DTIC

Arm B: Gemcitabine + DTIC

p = 0.014

[0.35 - 0.897]0.563[8.78 Š 24.88]16.8 m.Arm B

Ź10.014

[6 Š 10.4]8.2 m.Arm A

CI 95%HRp valueCI 95%OS median

Treatment Schedule: ARM A: DTIC 1200 mg/m2 q 21 days ARM B: Gemcitabine 1800 mg/m2/min + DTIC 500 mg/m2 q 14 days Study Design: 113 pts. Randomized phase II study. Endpoint: PFR at 3 months

E. turbinata

ET-743 se une de forma covalente con G nucleotidos en el surco menor del DNA, inclinando la hélice de DNA.

Interacciona con factores de transcripción y con proteínas de unión al DNA

Altera el ciclo celular: G2/M bloqueo Interfiere con vías de reparación del DNA

Macrophages PMNs T cells0

25

50

75

UntreatedTreated

**

*% o

f cel

ls /

CD

45+

Macrophages PMNs T cells0

10

20

30

40

50

60

70

UntreatedTreated

**

% o

f CD

45+

cells

MN/MCAI LLC

Macrophages PMNs T cells0

10

20

30

40

50

60

70

UntreatedTreated

*

*

% o

f CD4

5+ c

ells

ID8

Untreated * Treated

MACROPHAGES VESSELS

Untreated * Treated

STUDY SCHEME ENDPOINT RESULTS

Phase II trial Uterine LMS (45)

Doxo 60 mg/m2 Trabectedin 1.2 mg/m2

DCR ORR 55% DCR 94% SD 39% PFS 12w 94%

Randomized Phase III in Translocation-related STS (n 121)

Doxo 75 mg/m2 or Doxo 60+I 6-9 Vs Trabectedin 1.5 mg/m2

PFS PFS 6M 60.7% vs 62.4%

Randomized Phase II trial in first line (n=115)

Doxo 60 mg/m2 Trabectedin 1.2 mg/m2 Vs Doxo 75 mg/m2

PFS ECCO-ESMO 2013

Sinovial Sarcoma

Lancet 2012 May 19;379(9829):1879-86

CONSISTENT BENEFIT IN PFS ACROSS ALL 3 STRATA

N (%) HR CI P-Value

Overall 369 (100%) 0.31 0.24-0.40 <0.0001

LEIOMYOSARCOMA 158 (43%) 0.31 0.20-0.47 <0.0001

SYNOVIAL 38 (10%) 0.19 0.23-0.60 0.0002

OTHER SPB 173 (47%) 0.36 0.25-0.52 <0.0001

Trabectedin Pazopanib Gemcitabine DTIC

Gemcitabine Docetaxel

ASTHENIA G3 FIRST 5 DAYS MILD DURABLE MILD G3-4 AFTER D8

MYELOTOXIC ++/+ + ++/+ ++/+++

GI CONSTIPATION DIARRHOEA STOMATITIS GI BLEEDING DIARRHOEA

ALOPECIA - - HAIR HIPOPIG - ++

NAUSEA +/++ +/++ ++ +

ANOREXIA ++/+ ++ - ´-/+

SPECIAL LIVER HYPERTENSION - DVT/PE

TERAPIAS DIRIGIDAS EN SARCOMAS NO GIST

IMATINIB: DFSP; CORDOMA; SVNP

SUNITINIB Tumor Fibroso Solitario

CRIZOTINIB Tumor Miofibroblástico Inflamatorio

M-TOR INH PEComas; Leiomiomatosis asociados Epstein Barr

PAZOPANIB Several

TRABECTEDIN LPS MIXOIDE; S SINOVIIAL

PARP INH S EWING (ONGOING)

NUTLINS WD/DD LIPOSARCOMA

WNT TBD

HEDGHOG/NOTCH TBD

DENOSUMAB TCG ÓSEO

ALK pathway relevant in IMT

MARCH 2012 OCTOBER 2012

Inflammatory Myofibroblastic Tumor

DFSP

Upcoming relevant New Treatments

ALDOXORUBICIN

LOCAL IMPACT TUMORS

GCTB

PVNS

IMMUNE TARGETS IN SARCOMA

Investigator Review

Aldoxorubicin Doxorubicin p

PFS 8.4 4.7 0.0002

HR 0.370 (0.212-0.643) 0.0004

PFR 6 m 67.1% 36.1% 0.008

ORR 24.0 5.3

S Cawla, J Clin Oncol 32:5s, 2014 (suppl; abstr 10502)

Independent Review

Aldoxorubicin Doxorubicin p

PFS 5.7 2.8 0.018

HR 0.586 (0.358-0.960) 0.034

PFR 6 m 46.8% 23.7% 0.038

ORR 23 0

S Cawla, J Clin Oncol 32:5s, 2014 (suppl; abstr 10502)

Giant Cell Tumor (GCT) of Bone

• Locally aggressive osteolytic neoplasm

• Composed of osteoclast-like giant cells (expressing RANK) and stromal cells (expressing RANKL)

• Associated with pain and impaired mobility and function

• Mimics other malignant bone tumors

Human RANK

Human RANKL

RANKL Expression in GCT After Denosumab Treatment

Pre-Treatment Week 25 Post-Treatment

Cells expressing RANKL (yellow arrows) adjacent to giant cells (red arrows)

No giant cells Fewer cells expressing RANKL adjacent to calcified material (blue arrow)

Distal Radius

CT 17/05/2009 CT 15/09/2009

Pigmented Villonodular Synovitis

W Tapp J Clin Oncol 32:5s, 2014 (suppl; abstr 10503^)

Pigmented Villonodular Synovitis

W Tapp J Clin Oncol 32:5s, 2014 (suppl; abstr 10503^)

Pigmented Villonodular Synovitis

W Tapp J Clin Oncol 32:5s, 2014 (suppl; abstr 10503^)

Pigmented Villonodular Synovitis

W Tapp J Clin Oncol 32:5s, 2014 (suppl; abstr 10503^)

Immune Targets in Sarcoma

Dasitinib & Ipilimumab in GIST (NCT01643278) ongoing • Imatinib decreased in vitro proliferation and activity of regulatory T cells

Vaccines against GM2, GD2, and GD3

Gangliosides in cell suface of sarcoma (NCT01141491) ongoing R phase II in adjuvant

PD-L1 expression in sarcoma and immune infiltrates • GIST and secondary Angiosarcoma promising

FasR + & p53 -

FasR - or p53 +

FasR - & p53 +

p=0.001

OVERALL SURVIVAL Relevance of FAS expression in sarcoma

J Martin, J Clin Oncol 32:5s, 2014 (suppl; abstr 10500)

javier.martin@ssib.es

www.cotmes.com