dr javier martin broto oncología médica hospital son...
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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)
