presentación de powerpoint · 2020. 8. 7. · o grade 3/4 aes, o dose reductions o treatment...
TRANSCRIPT
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Máster en Tumores Musculoesqueléticos
Título
Universidad Europea de Madrid (UEM)
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Máster en Tumores Musculoesqueléticos
Caso clínico
• Mujer de 55 años fumadora, perimenopaúsica
• Antecedente de hipotiroidismo
• Junio 2018 metrorragias y dolor abdominal
• Valorada por Ginecología: sept 2018 masa uterina
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Máster en Tumores Musculoesqueléticos
Noviembre 2018
• 9 de Noviembre 2018
• Histerectomía
• AP: UTERO: LEIMOISARCOMA EPITELOIDEO QUE AFECTA A CUERPO, CUELLO UTERINO, Y TROMPAS.
• EXTENDIÉNDOSE POR PARAMETRIOS DERECHO E IZQUIERDO. Margen afecto
• PRESENCIA DE INVASIÓN VASCULAR Y NECROSIS.
• 11 MITOSIS POR 10CGA.
• LAS CÉLULAS NEOPLÁSICAS MUESTRAN POSITIVIDAD PARA: VIMENTINA, CALDESMÓN, ACTINA (focal),
• INDICE PROLIFERATIVO (Ki-67) DEL 80%.
• AUSENCIA DE EXPRESIÓN PARA: CKAE1/AE3, C-KIT, CD34.FLI-1.
• No MSI
• Receptores negativos3
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Máster en Tumores Musculoesqueléticos
Remitida a Oncología
• Si hubiese sido localizado
• 1. Cirugía correcta? Anexectomía? Linfadenectomía?
• Tratamiento adyuvante?
• Radioterapia?
• Quimioterapia?
• Diapos adyuvancia
4
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Máster en Tumores Musculoesqueléticos
Tratamiento. Tumor localizado
• Cirugía: histerectomía total
• Doble anexectomía si afectación macroscópica
• Afectación ganglionar rara ( 6-9%)
• Linfadenectomía si afectación macroscópica o afectación extrauterina
• Cirugía no planeada (histerectomía subtotal o morcellation) se aconseja nueva cirugía (upstaging15%)
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Máster en Tumores Musculoesqueléticos
https://www.mskcc.org/nomograms/uterine
Zivanovic O, Jacks LM, Iasonos A, et al. A nomogram to predict postresection 5-year overall survival for patients with
uterine leiomyosarcoma. Cancer. 2012 Feb 1;118(3):660-9. doi: 10.1002/cncr.26333. Epub 2011 Jul 12.
Iasonos A, Keung EZ, Zivanovic O, et al. External validation of a prognostic nomogram for overall survival in women
with uterine leiomyosarcoma. Cancer. 2013 May 15;119(10):1816-22. doi: 10.1002/cncr.27971. Epub 2013 Mar 1.
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Máster en Tumores Musculoesqueléticos
Problemas para interpretar estudios de adyuvancia en uLMS
• Estudios pequeños
• Con frecuencia análisis de casos o estudios retrospectivos
• Fase II
• Mezcla de estadios
• Mezcla de localizaciones
• Mezcla de histologías
• Con frecuencia se cierran por falta de reclutamiento
• Difícil sacar conclusiones
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
Quimioterapia adyuvante
Mortalidad 5% por quimioterapia
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
Conclusiones: leiomiosarcoma uterino localizado
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Máster en Tumores Musculoesqueléticos
Oncología Enero 2019
• 1. Tenía indicación de cirugía uterina siendo metastásica?
• TAC Enero 2019: progresión pulmonar y local
• Función cardiaca normal
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Máster en Tumores Musculoesqueléticos16
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Máster en Tumores Musculoesqueléticos
Opciones primera línea tratamiento quimioterápico
• Opciones de tratamiento:
• Adriamicina
• Adriamicina Olaratumab
• Adriamicia- Ifosfamida
• Adriamicina DTIC
• Gemcitabina Taxotere
• Otros
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Máster en Tumores Musculoesqueléticos
Phase 3 Trials in Advanced STS
PALETTE1
pazopanib vs. placebo
mOS: 12.5 vs. 10.7 moHR: 0.86
(95% CI, 0.67-1.11)
PFS: 4.6 vs. 1.6 mo
dox, doxorubicin; doce, docetaxel; EORTC, European Organisation for Research and Treatment of Cancer; GEDDIS, gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas; mOS, median overall survival; mo, month; PICASSO, palifosfamide-tris with doxorubicin for soft tissue sarcoma; SARC, Sarcoma Alliance for Research Through Collaboration; STS, soft tissue sarcoma; wks, weeks.
GeDDiS7
dox vs. doce + gemcitabine
mOS: 17.6 vs. 15.5 mo
HR: 1.14(95% CI, 0.83-1.57)PFS: 23.3 vs. 23.7
wks
SARC 216
dox vs. dox + evofosfamide
mOS: 19.0 vs. 18.4 mo
HR: 1.06 (95% CI, 0.88-1.29)PFS: 6.0 vs. 6.3 mo
EORTC-620122
dox vs. dox + ifosfamide
mOS: 12.8 vs. 14.3 mo
HR: 0.83(95% CI, 0.67-1.03)PFS: 4.6 vs. 7.4 mo
PICASSO-III3
dox vs. dox + palifosfamide
mOS: 16.9 vs. 15.9 mo
HR: 1.05(95% CI, 0.79-1.39)PFS: 5.2 vs. 6.0 mo
2014 2015 201720162012
First Line Second Line + Third Line +
Led to drug approval
1. Van der Graaf et al. Lancet 2012; 2. Judson I et al. Lancet Oncol 2014; 3. Ryan et al. J Clin Oncol 2016; 4. Trabectedin US prescribing information 2019; 5. Schöffski et al. Lancet 2016; 6. Tap et al. Lancet Oncol 2017; 7. Seddon et al. Lancet Oncol 2017
W Tap. ASCO 2019
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Máster en Tumores Musculoesqueléticos
• DOX + IFO vs DOX:•
o Median follow-up: 59 vs 56 mos
o 1-year OS: 60% vs 51%
o 2-year OS: 31% vs 28%
o ORR: 26% vs 14%; P = .0006 •
• Pts in DOX + IFO more: •
o grade 3/4 AEs,
o Dose reductions
o Treatment interruptions/ discontinuations
•
• Pts in DOX arm more likely to receive post-protocol IFO
Judson I, et al. Lancet Oncol. 2014;15:415-423.
100
80
60
40
20
0
OS
(%
)
100
80
60
40
20
0
PF
S (
%)
60540 6 12 18 24 30 484236
0 5 10 15 20 25 30 35 40
Mos
Mos
Median PFS, Mos
DOX + IFO
DOX7.4
4.6HR: 0.74 (95% CI: 0.60-
0.90; P = .003)
Median OS, Mos
DOX + IFO
DOX14.3
12.8HR: 0.83 (95% CI: 0.67-
1.03; P = .076)
EORTC 62012: Efficacy
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Máster en Tumores Musculoesqueléticos
Acta Oncologica, 56:7, 1013-1020
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Máster en Tumores MusculoesqueléticosB Seddon Lancet Oncol 2017
• Rx withdrawals:
• GEM + DTX = 63%
• DOX = 47%
• Due to toxicity:
• GEM + DTX = 13/80 (16%);
• DOX = 1/60 (2%)
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Máster en Tumores Musculoesqueléticos
GeDDiS: La combinación de gemcitabina-docetaxel no es
superior a la adriamicina, incluso en los leiomiosarcomas
Gemcitabina + docetaxel(n = 128)
Adriamicina(n = 129)
HR (95% CI)
Valor p
Mediana de SLP, meses
5.5 5.41.28
(0.98-1.67).07
SLP a 24 meses, % 46.0 46.1
Mediana de SG, meses
14.5 16.41.07
(0.77-1.49).67
SG a 24 semanas, % 82.5 86.7
HR (95% CI), Gemcitabina-docetaxel vs
adriamicina
Valor p de la interacción
Leiomiosarcoma (n = 118) 1.12 (0.75-1.66) .326
Nonleiomiosarcoma (n = 139) 1.46 (1.02-2.09)
Análisis de subgrupos, SLP
Seddon BM, et al. ASCO 2015. Abstract 10500.
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Máster en Tumores Musculoesqueléticos
Olara + Doxo in uLMS
Olara+dox Dox
Patients/Events 8/5 7/5
Median, months 25.0 11.4
(95% CI) (4.9, n/e) (3.6, n/e)
Unstratified HR (95% CI) 0.61 (0.175, 2.144)
Olara+dox Dox
Patients/Events 8/7 7/4
Median, months 2.7 3.6
(95% CI) (1.1, 11.0) (1.0, n/e)
Unstratified HR (95% CI) 0.93 (0.245, 3.541)
Progression-Free
SurvivalOverall Survival
van Tine BA, et al. Gyn Oncol 2017; 145 (Suppl 1): #190 (2017 Ann Meet Society Gyn Oncology)
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Máster en Tumores Musculoesqueléticos
Olaratumab + Doxorubicin:Overall Survival: tSTS and LMS Populations
© 2019 Eli Lilly and Company
Dox, doxorubicin; LMS, leiomyosarcoma; Olara, olaratumab; OS, overall survival; Pbo, placebo; tSTS, total Soft Tissue Sarcoma W Tap. ASCO 2019
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Máster en Tumores Musculoesqueléticos
Guías ESMO: opción de Adr- DTIC
Sin embargo , en el
estudio randomizado de
Antman de 1993
(ADR+DTIC vs ADI)
RR de AD 17%
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Máster en Tumores Musculoesqueléticos26
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Máster en Tumores Musculoesqueléticos
Evolución
• Adriamicina 75 mg/m2 x 3 ciclos
• Abril 2019 progresión pulmonar y local con hidronefrosis derecha.
• ECOG 1
• Metrorragia, Hb 10,7, LDH 274(N<240)
• Opciones:
• Gemcitabina- DTIC
• Gemcitabina- TXT
• Trabectedina
• Pazopanib
• Randomizados
• Beneficio de pazopanib
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Máster en Tumores Musculoesqueléticos
Phase 3 Trials in Advanced STS
PALETTE1
pazopanib vs. placebo
mOS: 12.5 vs. 10.7 moHR: 0.86
(95% CI, 0.67-1.11)
PFS: 4.6 vs. 1.6 mo
dox, doxorubicin; doce, docetaxel; EORTC, European Organisation for Research and Treatment of Cancer; GEDDIS, gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas; mOS, median overall survival; mo, month; PICASSO, palifosfamide-tris with doxorubicin for soft tissue sarcoma; SARC, Sarcoma Alliance for Research Through Collaboration; STS, soft tissue sarcoma; wks, weeks.
PALETTE1
pazopanib vs. placebo
mOS: 12.5 vs. 10.7 mo
HR: 0.86 (95% CI, 0.67-1.11)
PFS: 4.6 vs. 1.6 mo
E7389-G000-3095
eribulin vs. dacarbazine
mOS: 13.5 vs. 11.5 mo
HR: 0.77(95% CI, 0.62-0.95)PFS: 2.6 vs. 2.6 mo
ET743-SAR-30074
trabectedin vs. dacarbazine
mOS: 13.7 vs. 13.1 mo
HR: 0.93 (95% CI, 0.75-1.15)PFS: 4.2 vs. 1.5 mo
2014 2015 201720162012
First Line Second Line + Third Line +
Led to drug approval
1. Van der Graaf et al. Lancet 2012; 2. Judson I et al. Lancet Oncol 2014; 3. Ryan et al. J Clin Oncol 2016; 4. Trabectedin US prescribing information 2019; 5. Schöffski et al. Lancet 2016; 6. Tap et al. Lancet Oncol 2017; 7. Seddon et al. Lancet Oncol 2017
W Tap. ASCO 2019
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
Trabectedin vs Dacarbazine: PFS by Histologic Subtype
Histologic Subtype Trabectedin,
Median PFS, Mos
(Events/Pts)
Dacarbazine,
Median PFS,
Mos (Events/Pts)
HR (95% CI)
Leiomyosarcoma 4.3 (154/252) 1.6 (85/126) 0.55 (0.42-0.73)
▪ Nonuterine 4.9 (70/118) 1.6 (28/48) 0.58 (0.37-0.92)
▪ Uterine 4.0 (84/134) 1.5 (57/78) 0.58 (0.41-0.81)
Liposarcoma 3.0 (63/93) 1.5 (27/47) 0.55 (0.34-0.87)
▪ Dedifferentiated 2.2 (35/45) 1.9 (16/25) 0.68 (0.37-1.25)
▪ Myxoid ± round
cell5.6 (21/38) 1.5 (8/19) 0.41 (0.17-0.98)
▪ Pleomorphic 1.5 (7/10) 1.4 (3/3) 0.33 (0.07-1.64)
Demetri GD, et al. J Clin Oncol. 2016;34:786-793.
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
Eribulin vs Dacarbazine: Key Results
Outcomes, MosEribulin
(n = 228)
Dacarbazine
(n = 224)
HR
(95% CI)P Value
Median OS 13.5 11.50.77
(0.62-0.95).0169
Median PFS 2.6 2.60.88
(0.71-1.09).2287
▪ Rate of grade ≥ 3 TEAEs higher with eribulin vs dacarbazine (67% vs 56%)
▪ Subgroup analysis showed activity of eribulin in liposarcoma
Median OS by Histologic
Subgroup, Mos (Events/Pts)Eribulin Dacarbazine HR (95% CI)
Liposarcoma 15.6 (52/71) 8.4 (63/72) 0.51 (0.35-0.75)
Leiomyosarcoma 12.7 (124/157) 13 (118/152) 0.93 (0.71-1.20)
Schöffski P, et al. Lancet. 2016;[Epub ahead of print].
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Máster en Tumores Musculoesqueléticos
• Abril 2019: gemcitabina TXT
• Trombopenia G3, anemia G2, diarrea G2, astenia G2, alopecia G2.
• Junio 2019 Hb 9,8
• Respuesta parcial
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Máster en Tumores Musculoesqueléticos
Evolución
• Agosto 2019 tras 6 ciclos ingreso con disnea. Se descarta TEP.
• TAC progresión pleuroplulmonar + d pleural por TXT?
• Trabectedina
• Gemcitabina DTIC?
• Pazopanib
• Otros?
36
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Máster en Tumores Musculoesqueléticos
• Agosto 2019 Trabectedina
• Tras dos ciclos ( Octubre 2019) ingreso por trombosis de cava.
• Se anticoagula y retira port a cath
• Opciones???
• Octubre 2019 comienza Temozolamida100 mg/m2 x 6 s cada 9 semanas
• Tras 1 ciclo diarrea grado 3
• Se baja dosis a 75mg/m2: sin toxicidad
• Enero respuesta parcial
• Mayo 2020 muy buena respuesta parcial
• Asintomática, sin toxicidad
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Máster en Tumores Musculoesqueléticos
Evolución
38
Nov 2018
cirugía
Enero
2019
progresión
Adr x 3Abril 2019
prog
Julio 19
RP
Gem
TXT Agosto
19
Prog
Gem
TXT Trabectedina
Oct 2019
Trombosis
cava
TemozolamidaMayo 2020 muy
buena respuesta
parcial
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Máster en Tumores Musculoesqueléticos
Alteraciones genéticas en sarcomas
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Máster en Tumores Musculoesqueléticos
Aberraciones genéticas en leiomiosarcomas
The Cancer Genome Atlas Research Network, 2017, Cell 171, 950–965
https://doi.org/10.1016/j.cell.2017.10.014
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Máster en Tumores Musculoesqueléticos
Lancet Oncol 2017; 18: 1493–1501
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
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Máster en Tumores Musculoesqueléticos
Foundation Medicine NGS panel
44
Temozolomida?
Otros alquilantes?
Platinos?
Trabectedina?
Inhibidores de PARP?
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Máster en Tumores Musculoesqueléticos
Phase 3 Trials in Advanced STS
PALETTE1
pazopanib vs. placebo
mOS: 12.5 vs. 10.7 moHR: 0.86
(95% CI, 0.67-1.11)
PFS: 4.6 vs. 1.6 mo
dox, doxorubicin; doce, docetaxel; EORTC, European Organisation for Research and Treatment of Cancer; GEDDIS, gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas; mOS, median overall survival; mo, month; PICASSO, palifosfamide-tris with doxorubicin for soft tissue sarcoma; SARC, Sarcoma Alliance for Research Through Collaboration; STS, soft tissue sarcoma; wks, weeks.
PALETTE1
pazopanib vs. placebo
mOS: 12.5 vs. 10.7 mo
HR: 0.86 (95% CI, 0.67-1.11)
PFS: 4.6 vs. 1.6 mo
GeDDiS7
dox vs. doce + gemcitabine
mOS: 17.6 vs. 15.5 mo
HR: 1.14(95% CI, 0.83-1.57)PFS: 23.3 vs. 23.7
wks
SARC 216
dox vs. dox + evofosfamide
mOS: 19.0 vs. 18.4 mo
HR: 1.06 (95% CI, 0.88-1.29)PFS: 6.0 vs. 6.3 mo
EORTC-620122
dox vs. dox + ifosfamide
mOS: 12.8 vs. 14.3 mo
HR: 0.83(95% CI, 0.67-1.03)PFS: 4.6 vs. 7.4 mo
PICASSO-III3
dox vs. dox + palifosfamide
mOS: 16.9 vs. 15.9 mo
HR: 1.05(95% CI, 0.79-1.39)PFS: 5.2 vs. 6.0 mo
E7389-G000-3095
eribulin vs. dacarbazine
mOS: 13.5 vs. 11.5 mo
HR: 0.77(95% CI, 0.62-0.95)PFS: 2.6 vs. 2.6 mo
ET743-SAR-30074
trabectedin vs. dacarbazine
mOS: 13.7 vs. 13.1 mo
HR: 0.93 (95% CI, 0.75-1.15)PFS: 4.2 vs. 1.5 mo
2014 2015 201720162012
First Line Second Line + Third Line +
Led to drug approval
1. Van der Graaf et al. Lancet 2012; 2. Judson I et al. Lancet Oncol 2014; 3. Ryan et al. J Clin Oncol 2016; 4. Trabectedin US prescribing information 2019; 5. Schöffski et al. Lancet 2016; 6. Tap et al. Lancet Oncol 2017; 7. Seddon et al. Lancet Oncol 2017
W Tap. ASCO 2019
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Máster en Tumores Musculoesqueléticos