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Ana de Juan Ferré
Oncología Médica
H. U. Marqués de Valdecilla
Santander
Optimizando el Tratamiento del Cáncer de Cérvix
Mesa Redonda 1
Diez años de avances en el tratamiento del cáncer ginecológico
Tres Grandes Hitos en la Última Década
1.
2.
3.
Una brevísima introducción…
HPV (Human papillomavirus)
VPH es un virus DNA de la familia Papovaviridae
De transmisión sexual
120 tipos descritos
Inhibe
Degrada
VPH 16 y 18
Responsables del 70% de CC
Int J Cancer 2017
85% de los nuevos diagnósticos ocurren en países subdesarrollados
2º cáncer en la mujer a nivel mundial; 6º tumor más frecuente en España
Tres Grandes Hitos en la Última Década
1. Estudio ATLAS
1.
2.
Alteraciones Moleculares Wright, Cancer 2013; Al Ojesina, Nature 2014
Gen Epidermoide, n 80 Adenocarcinoma, n 40 p
PI3K 37,5% 25% 0,33
PTEN 13 % 3,6% 0,32
kRAS 0 17,5% 0,01
EGFR 7,5% 0 0,24
Nature 2017
Se caracterizan molecularmente 228 CC 14 genes mutaciones recurrentes - 9 conocidos: PIK3CA, EP300, FBXW7,
PTEN, ARID1A, NFE2K2, HLA-B, KRAS, MAPK1
- 5 nuevos SHKBP1, ERBB3, CASP8, HLA-A, TGFBR2
Mutaciones mediadas por APOBEC 1026 genes silenciados epigenéticamente (metilaciones) Amplificaciones de dianas de inmunoterapia (PD-L1, PD-L2) y de BCAR4 (asociado a respuesta con lapatinib) CC endometrial-like (HPV negativos): KRAS, ARID1A, PTEN
Queratina Queratina Adenocarcinomas
Tres Grandes Hitos en la Última Década
1. Estudio ATLAS
2. Incorporación de
Bevacizumab
3.
Cáncer Cérvix – Enfermedad Avanzada
Lo Conocido respecto a la QT en 1ª Línea
1. La dosis recomendada de cisplatino es de 50
mg/m2
- Bonomi P. J Clin Oncol 1985
2. Combinación con cisplatino mejor que monoterapia
- Omura GA et al. J Clin Oncol 1997
- Moore DH et al. J Clin Oncol. 2004
- Long HJ et al. J Clin Oncol. 2005
- Monk BJ, et al. J Clin Oncol 2009
3. Carboplatino y paclitaxel como estándar, si
cisplatino previo - Kitagawa R. J Clin Oncol 2015
“Combo” mejor que monoterapia
Estudio n Respuestas SLP, meses SG, meses
GOG 1101
CDDP
CDDP-IFX
140
151
19%
31%
3,2
4,6
8
8,3
GOG 1692
CDDP
CDDP-Pac
134
130
19%
36%
3
4,9
8,9
9,9
GOG 1793
CDDP
CDDP-Topo
145
148
13%
26%
2,9
4,6
7
9,2
GOG 2044
CDDP-Pac CDDP-VNR
CDDP-Gemc
CDDP-Topo
103
108
112
111
29,1%
25,9%
22,3%
23,4%
5,82
3,98
4,70
4,57
12,87
9,99
10,28
10,25
1. Omura GA et al. J Clin Oncol 1997; 2. Moore DH et al. J Clin Oncol. 2004; 3. Long HJ et al. J Clin Oncol. 2005; 4. Monk BJ, et al. J Clin Oncol 2009
Supervivencia Libre Progresión Supervivencia Global
Carboplatino – Paclitaxel artralgias, mialgias, neuropatía, menos hospitalizaciones
Cisplatino – Paclitaxel fiebre neutropénica, función renal, náuseas/vómitos
JGOG 0505 Kitagawa R. J Clin Oncol 2015
Cisplatino-Paclitaxel frente Carboplatino-Paclitaxel
Análisis
por Subgrupos
Si no ha recibido Cisplatino previo Mejor Cisplatino y Paclitaxel
JGOG 0505 Kitagawa R.
J Clin Oncol 2015
Factores Pronósticos, Moore DM. Gynecol Oncol 2010
OR IC 95% p
Raza negra vs no 0,49 0,28-0,83 0,008
PS 1-2 vs PS 0 0,60 0,38-0,94 0,027
Pelvis vs Otra 0,58 0,38-0,90 0,015
Radiosens. vs no 0,52 0,32-0,85 0,009
Rec. <1 vs >1 año 0,61 0,39-0,95 0,027
SG según Factores de Riesgo
Riesgo Bajo: 0-1; Riesgo Moderado: 2-3; Riesgo Alto: 4-5
The GOG experience: 12-month milestone
survival rates in pretreated PRmCC
GOG, Gynecologic Oncology Group, now NRG Oncology; PRmCC, persistent/recurrent metastatic cervical cancer.
Tewari KS, et al. Curr Oncol Rep. 2005;7(6):419-434; Muggia F, et al. Gynecol Oncol. 2004;92(2):639-643; Plaxe SC, et al. Cancer Chemother Pharmacol.
2002;50(2):151-154; Armstrong DK, et al. Invest New Drugs. 2003;21(4):453-457; Fracasso PM, et al. Gynecol Oncol. 2003;90(1):177-180; Brewer CA, et al. Gynecol
Oncol. 2006;100(2):385-388; Rose P, et al. Gynecol Oncol. 2006;102(2):210-213; Garcia AA, et al. Am J Clin Oncol. 2007;30(4):428-431; Miller DS, et al. Gynecol Oncol.
2008;110(1):65-70; Fiorica JV, et al. Gynecol Oncol. 2009;115(2):285-289; Monk BJ, et al. J Clin Oncol. 2009;27(7):1069-1074; Schilder RJ, et al. Int J Gynecol Cancer.
2009;19(5):929-933; National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=691288. Accessed February 6, 2016.
5
Opciones Terapéuticas en Cáncer de Cérvix Avanzado
Cervicitis crónica
Carcinoma infiltrante
Carcinoma in situ (CIN)
Displasia
VEGF
HIF-1α
HPV
E6 y E7
p53, pRb
degrada
Inhibe
Cáncer de Cérvix – Historia Natural
GOG 240, Tewari KS. NEJM 2014
Obj. Primario: Si la adición de Beva mejora SG; si un régimen sin platino mejora SG
Obj. Secundarios: SLP, Toxicidades, QOL
Diseño factorial 2x2
Características Sólo QT (n 225) % QT y Beva(n 227), %
Edad media, años 46 (20-83) 48 (22-85)
Histología %
- Escamosa
- adenocarcinoma
68
20
70
19
Etapa %
- Recaída
- Persistencia
- Avanzado
73 10
16
75 16
5
Performance status %
0
1
58
42
58
42
Platino previo % 74 75
Enfermedad Pélvica % 53 54
GOG 240, Tewari KS. NEJM 2014
GOG 240, Tewari KS. NEJM 2014
Supervivencia Global Supervivencia Libre Progresión
Lancet 2017
Supervivencia Global
16,8 m frente 13,3 m
Sin diferencias
Calidad de Vida
Lancet 2017
Supervivencia Global post-progresión
Fístulas (cualquier grado)
15% frente 1%
Fístulas g3
6% frente <1%
Todas RT previa
Ninguna requiere
cirugía urgente, sepsis
o desenlace muerte
Sin efecto rebote
GOG 240: Impacto del Bevacizumab según Grupos Pronósticos Tewari KS, Clin Cancer Res 2015
Riesgo Bajo
Riesgo
Moderado
Riesgo
Alto
Toxicidades con adición Beva - HTA ≥ g2: 25% frente 2%
- Fístula: GI 3%; GU 3%
- Neutropenia g4: 35% frente 26%
- TEP: 8% frente 1%
Otros Antiangiogénicos
Referencia Fármaco Estudio Población Resultados
Monk BJ J Clin Oncol 2010
J Clin Oncol 2011
Pazopanib
Lapatinib
Pazo- Lapa
Fase II
N 228
IVb
Recaída
Combo toxicidad
inaceptable
Pazo mejor RR, SLP y
SG
Mackay HJ. Gynecol Oncol 2010
Sunitinib Fase II
IND.184
N 19
Localmente
Avanzado,
M1, recaída
Sin respuestas
EE 84%; SLP 24,6 s
Fístula 26%
Symonds RP Lancet Oncol 2015
Carbo-Pac
± Cediranib
Fase II
CIRCCa
N 69
Recaída,
M1
Mejor SLP con
cediranib, carbo y pac
No diferencias en SG
Chan JK Gynecol Oncol 2017
Brivanib
Fase II
GOG-227G
Recaída
M1
Suspendido
BGOG-
cx1/ENGOT-cx1
Carbo-Pac
± Nintedanib
Fase II Recaída
M1
Ongoing
Tres Grandes Hitos en la Última Década
1. Estudio ATLAS
2. Incorporación de
Bevacizumab
3. Inmunoterapia:
Prevención y
Tratamiento
Vacunas Profilácticas
3 vacunas elaboradas con “Virus-Like Particles” (VLP) del fragmento
L1 de la cápside del VPH, inmunogénico no oncogénico
Cervarix® (GSK) (HPV-023, PATRICIA, COSTA RICA) Bivalente (16 y 18)
Sintetizada en baculovirus
Tres dosis im a los 0, 1 y 6 meses
Sal de aluminio y monofosforil lípido A (MPL) como adyuvante
Gardasil® (MSD) (FUTURE I y II, HPV-p-007) Tetravalente (6, 11, 16, 18)
Sintetizada en levaduras
Tres dosis im a los 0, 2 y 6 meses
Sal de aluminio como adyuvante
Gardasil 9 (MSD) (Joura EA, N Engl J Med 2015) Nonavalente (6, 11, 16, 18, 31, 33, 45, 52, 58)
Sintetizada en levaduras
Tres dosis im a los 0, 2 y 6 meses
Sal de aluminio como adyuvante
Lancet 2017
N 14215 de Sep-07 a Dic-09; 105 centros, 18 países Mujeres de 16-26 años sanas Nonavalente frente Tetravalente Objetivos - Incidencia de CIN 2-3, ADCis, CIS; VIN 2-3 y
CV; VAIN 2-3 y Cva relacionado con HPV 31, 33, 45, 52, 52
0,5/100000 (9vHPV) frente 19/100000 (qHPV) 97,4% eficacia
- no inferioridad de HPV 6, 11, 16 y 18 Sin diferencias toxicidad
Opciones Terapéuticas Prendergast GC, et al. Trends in Cancer 2018
Tipo Vacuna Diana
Vacuna basada en
vectores vivos
atenuados
(bacterias y virus)
ADXS11-001 (bacteria)
TA-HPV (virus)
VPH-16 E7 proteína fusión
VPH-16 E6 y péptido E7
Péptido HLA-A*201 VPH-16 E7 péptido
Proteína SNG-00101 Proteína fusión VPH-16 E7
Ácido Nucleico ZYC101a
VGV-3100a
VPH 16 E7 HLA-A2 péptido
VPH-16 y 18 E6 y E7
Vacunas Terapéuticas, Eskander RN, et al. Clin Ther 2015
Listeria monocytogenes (Lm)
Infecta macrófagos y
Evade fagosoma gracias
Listeriolisina O (LLO)
Péptidos derivados de Lm
Son presentados por CHM I y II
E inducen respuestas mediadas por CD4 y CD8
ADXS11(Ag fusión E7 y LLO), Eskander RN, et al. Clin Ther 2015
Autor Estudio Respuestas Toxicidades
Maciag PC.
Vaccine 2009
Fase I, n 15
Muy pretratadas
61,5% BC (53,8%
EE)
Fiebre, emesis,
“flu-like”
Basu P.
ASCO 2014
Fase II, n 110
Estudio Hindú
Recaída y
refractaria
Vacuna ± CDDP
43% BC (6 RC, 6
RP, 35 EE)
DOR 10,5 m
SG a 18 m: 28%
SG a 12 m: 36%
Fiebre, emesis,
“flu-like”
Huh W.
SGO 2017
Fase II
Estudio GOG 265
Persistente,
recaída
SLP a los 12 m:
38%
Síndrome
pseudogripal,
anemia
ADXS11(Ag fusión E7 y LLO)
GOG 0265 A prospective Phase 2 trial of the Listeria-based HPV inmunotherapy axalimogene filolisbac (AXAL)
in second- and third-line metastatic cervical cancer: An NRG Oncology Group trial
GOG/NRG-0265: Study design and eligibility
†N = total 54 enrolled, as a result of clinical hold interruption during Stage 2.
*Stage 2 amended to allow continuous (>3) dosing of AXAL.
AXAL, axalimogene filolisbac; CFU, colony-forming units; GOG PS, Gynecologic Oncology Group performance status; HPV, human papillomavirus;
ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRmCC, persistent/recurrent metastatic cervical cancer; RECIST,
Response Evaluation Criteria In Solid Tumors.
8
N 63, ≥ 18 años, PS 0/1, enfermedad medible (RECIST 1.1); Ca. cérvix enf. avanzada, ≥ 1 línea
de QT (se permitía beva previo)
Objetivo 1arios: Tasa supervivencia a 12 m y seguridad/tolerabilidad; 2arios: SLP, SG y respuestas
Overall (N = 50)
Median age (range), years 46 (29–70)
Race, n (%)
White 37 (74)
GOG PS, n (%)
0 vs 1 31 (62) vs 19 (38)
FIGO stage at diagnosis, n (%)
IA
IB
IIA
IIB
IIIB
IV
Not available
1 (2)
18 (36)
3 (6)
14 (28)
4 (8)
10 (20)
1 (2)
Prior lines of systemic-dose therapy, n (%)
1
2
3
24 (48)
22 (44)
4 (8)
Prior bevacizumab, n (%) 28 (56)
Prior pelvic radiation, n (%) 43 (86)
Demographics and baseline characteristics
Note: Prior lines of therapy do not include chemotherapy given as part of curative treatment.
FIGO, International Federation of Gynecology and Obstetrics; GOG PS, Gynecologic Oncology Group performance status.
11
Treatment-emergent adverse event summary
• All t
r
ea ted patients (N = 50 ) ex perienced ≥1 AE;; s a fety findings from both
stages of the study were consistent
AE Grade 1–4 Grade 1–2 Grade 3 Grade 4
Patients with
≥1 TRAE, n (%)48 (96) 28 (56) 18 (36) 2 (4)*
TRAEs occurring in ≥30% of patients
Fatigue 26 (52) 26 (52) - -
Chills 26 (52) 26 (52) - -
Anemia 24 (48) 19 (38) 5 (10) -
Nausea 16 (32) 16 (32) - -
Fever 15 (30) 15 (30) - -
*The observed grade 4 TRAEs recorded in 2 patients were considered possibly related (lung infection [klebsiella related] and
sepsis; same patient) or probably related (hypotension and cytokine related symptoms; same patient) to treatment.
AE, adverse event; TRAE; treatment-related AE.
12
GOG 0265 A prospective Phase 2 trial of the Listeria-based HPV inmunotherapy axalimogene filolisbac (AXAL)
in second- and third-line metastatic cervical cancer: An NRG Oncology Group trial
CI, confidence interval; OS, overall survival.
• Represents a 52%
improvement vs logistic
model-predicted milestone
survival rate of 24.5%
• The probability of this
survival advantage being
detected by chance vs a
true treatment effect was
0.02
• 8 patients remain alive as of
January 31, 2017
12-month and median overall survival1
0.9
0.4
0.2
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24
Ove
rall
su
rviv
al
Months
26 28 30 32 34 36 38 40 42
0.8
0.7
0.6
0.5
0.3
0.1
12-month OS rate: 38%,
range 12.02–40.6 months
(n = 19/50; primary endpoint)
50 47 35 25 22 21 19 13 9 4 3 3 3 3 3 3 2 1 1 1 1 0
Number of patients: 50
Events: 42 (84%)
Censored: 8 (16%)
Median OS: 6.2 months
95%CI: (4.4–12.3)
No. at risk:
13
Pembrolizumab (anti-PD-1): KEYNOTE-028 (Fase Ib, n 24) Frenel JS. J Clin Oncol 2017
Características pacientes
- N 24 (23 epidermoides)
- RT previa 96% (QT-RT previa 23)
- Líneas previas
1 38%; 2 25%; 9 38%
- Platino previo 96%
- Beva previo 42% (n 10)
Respuestas
- RP 17% - EE 13%
- Progresión 67%
Respuestas duraderas, mediana DOR 26 semanas, algunas de 1 año
Nivolumab: CheckMate 358 (Fase I/II, n 24) Hollebecque A, et al. ASCO 2017, #5504
Transferencia TIL, Eskander RN, et al. Clin Ther 2015
Anticuerpo Conjugado Vedotin-Tisotumab Vergote I, et al. ESMO 2017
TISOTUMAB VEDOTIN MECHANISM OF ACTION
4
• Tisotumab vedotin is an Antibody-Drug Conjugate (ADC) composed of a human mAb specific for Tissue Factor (TF), a protease-cleavable linker, and the microtubule disrupting agent MMAE1,a,b
• TF is a transmembrane protein that is the main physiological initiator of coagulation and is involved in angiogenesis, cell adhesion, motility, and cell survival3
• TF is aberrantly expressed in a broad range of solid tumours, including cervical cancer, and is associated with poor prognosis4,5
ADC=antibody-drug conjugate; mAb=monoclonal antibody; MMAE=monomethyl auristatin E.aTissue factor is known as TF, CD142, and thromboplastin.bMMAE-based ADC technology was licensed from Seattle Genetics, Inc., in a license and collaboration agreement.
1. Breij EC et al. Cancer Res. 2014;74(4):1214-1226. 2. De Goeij BE et al. Mol Cancer Ther. 2015;14(5):1130-1140. 3. Chu AJ. Int J Inflam. 2011;2011. doi: 10.4061/2011/367284.
4. Förster Y et al. ClinChimActa. 2006;364(1-2):12-21. 5. Cocco E et al. BMC Cancer. 2011;11:263.
Mechanism of action1,2
1. Binding to TF
2. Internalization of
tisotumab vedotin
3. Intracellular trafficking to
the lysosomes
4. Enzymatic degradation of
tisotumab vedotin,
intracellular release of MMAE
5. MMAE induces cell death
by microtubule disruption
6. Release of MMAE in tumour
microenvironment induces bystander
killing of neighbouring cancer cells
Fase II Anticuerpo Conjugado Vedotin-Tisotumab Vergote I, et al. ESMO 2017, #9310 GEN701 IS THE FIRST-IN-HUMAN STUDY OF TISOTUMAB VEDOTIN
CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NSCLC=non–small cell lung cancer; SCCHN=squamous cell carcinoma of the head and neck.aSubjects were enrolled into cohorts at increasing dose levels of tisotumab vedotin in 21-day treatment cycles. bIn phase 2, ovarian and cervical cohorts were expanded to approximately
30 patients based on preliminary efficacy observed in the first 14 patients enrolled. cThe SCCHN cohort was closed by protocol amendment 4 due to an event of pharyngeal tumour
haemorrhage with fatal outcome. The event was deemed to be most likely related to the disease itself.
Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02001623. Accessed August 7, 2017.
Key inclusion criteria:
• Patients with relapsed, advanced, and/or
metastatic cancer who have failed
available standard therapy
• Measurable disease
Key exclusion criteria:
• Abnormal coagulation parameters at
baseline
• Ongoing major bleeding
• Presence of CTCAE grade
≥2 peripheral neuropathy
• 3+3 dose-escalation designa
• Dose range tested: 0.3-2.2 mg/kg IV q3w
• Patients enrolled included those with the
following tumour types (N=27):
• Gynaecologic (ovarian, cervical,
and endometrial)
• Prostate
• Bladder
• Oesophageal
• NSCLC
• SCCHNc
• Ongoing expansion cohort
• Dose selected: 2.0 mg/kg IV q3w
Part 1: Dose escalation Part 2: Expansion cohort
Bladder (n=15)
Oesophageal (n=15)
Prostate (n=18)
Cervical (n=34)b
Ovarian (n=36)b
Endometrial (n=14)
• Primary endpoint: Safety and tolerability
• Key secondary endpoints: Anti-tumour activity
6
NSCLC (n=15)
76% ECOG 1
44% Adenocarcinoma
53% ≥2 líneas previas
(91% bevacizumab)
74% RT previa
32% OF PATIENTS WITH RECURRENT/ADVANCED CERVICAL CANCER ACHIEVED RESPONSE WITH TISOTUMAB VEDOTIN
12
CI=confidence interval; CR=complete response; CT=computed tomography; DCR=disease control rate; ORR=overall response rate; PD=progressive disease; PR=partial response;
RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.aTwo patients were withdrawn prior to CT scan, and so are not represented in the graph. bPD due to new lesion at same scan. cClinical benefit was defined as the DCR rate, the proportion of patients
who achieved a CR, PR, or SD after 12 weeks. dResponse was as assessed by investigators using standard RECIST 1.1 criteria. eOne of which is still ongoing. Data cutoff date July 24, 2017.
PR
b b b b
• 50% (17 of 34 patients; 95% CI, 35%-65%) achieved clinical benefit after 12 weeks (DCR)c,d
• 32% (11 of 34 patients; 95% CI, 17%-50%) achieved response (ORR)d
− 8 PR, confirmed
− 3 PR, unconfirmede
Change at first scan
Maximum reduction
N=34a
Best Perc
ent C
hange
Fro
m B
aseline, % Confirmed response
32%
Respuestas DURATION OF RESPONSE WITH TISOTUMAB VEDOTIN
IN CERVICAL CANCER COHORT
14
DoR=duration of response; NE=not evaluated; PD=progressive disease; PFS=progression-free survival; PR=partial response; SD=stable disease.aPatient withdrawn. b 4 responders have progressed as of the data cutoff of July 24, 2017 and 4 have been withdrawn because of other reasons and are thus censored for DoR. cEstimated median PFS was 6.4 months.
Data cutoff date July 24, 2017.
Months
Indiv
idual
Pat
ients
a
• Median DoR of confirmed response is 8.3 months (95% CI; 2.1, -) and 5.3 months for confirmed and unconfirmed responses (95% CI; 1.5, 10.0)b
• 7 patients are ongoingc
PD
SD PR
N=34
Ongoing
PDNE
Discontinuation, no PD
8,3 m Duración Respuesta
Ojo con la Conjuntivitis
Prevalencia de HRD en todos los tumores Heeke A, et al. ASCO 2017
Methods
AIM: Determine prevalence of HRD among all
tumor lineages
• 53,619 solid tumors evaluated
• Patient population: advanced malignancy, typically
refractory to chemotherapy
• HRD defined: pathogenic or presumed pathogenic
somatic mutation of ATM, ATRX, BARD1, BLM,
BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A,
NBN, PALB2, PTEN, RAD50, RAD51,
RAD51B, or WRN
Presented by: Arielle Heeke, MD
Lineage N
Ovarian 8,868
NSCLC 7,423
CRC 6,267
Breast 5,785
Endometrial 5,189
Pancreas 2,019
Melanoma 1,792
Sarcoma 1,760
Glioma 1,672
Unknown Primary 1,466
Neuroendocrine 1,440
Gastroesophageal 1,426
Cholangiocarcinoma/HCC 830
Cervix 791
Prostate 690
Head/Neck 642
Bladder 233
Kidney 219
GIST 201
Thyroid 191
53619 tumores sólidos refractarios a QT
HRD Mutación somática (presumiblemente) patogénica de
ATM, ATRX, BARD1, BLM, BRCA ½, BRIP,
FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN,
RAD50, RAD51, RAD51B, WRN Results, Total HRD mutation frequency by lineage
14.1
9.7
8.0 7.4 7.1
6.5 6.4 6.3
5.2 5.1 4.8 4.8 4.3 4.0
2.8 2.6 2.2 1.9
1.4 1.3
0
5
10
15
HR
D M
uta
tio
n F
req
ue
nc
y
(%)
Lineage
Presented by: Arielle Heeke, MD
J Clin Oncol 2017
N 26 (2 CC)
Durva y olara 2 RP y 83% BC
Durva y cedi 6 RP y 75% BC
Avances Terapéuticos en Cáncer de Cérvix
Conclusiones
Tewari KS, et al. Clin Cancer Res 2015
1. Conocimiento Molecular
2. Incorporación del Bevacizumab
3. La inmunoterapia como futuro próximo
Muchas gracias