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Avances Terapéuticos en el Tratamiento de los
Tumores Ginecológicos: Papel de la Angiogénesis
Ana Oaknin, MD
Medical Oncology Department. Gyneacological Cancer Unit
Vall d´Hebron University Hospital. Vall d’Hebron Institute of Oncology
Barcelona, Spain
[email protected]
Gynecologic Tumors(GYNT): Epidemiology
 GYNT comprises 19% of new
cancer cases each year.
 Endometrial cancer is the GYNT
most common.
 Cervical Cancer is the second
most common cancer in women
after breast cancer .
 Ovarian cancer is the fifth cause
of cancer death and the most
lethal GYNT
Source: American Cancer Society. Cancer Facts&Figures 2013.
The angiogenic switch in tumour development
Tumour Vasculature effect
Small tumour (1–2mm)
Larger tumour
• Avascular
• Vascular
• Dormant
• Metastatic potential
Angiogenic switch
Results in over-expression
of pro-angiogenic signals,
such as VEGF
Bergers G. et al . Nature Reviews Cancer 2003;3:401–10.
Bergers, et al. Nature 2002
Therapeutic Targeting of Angiogenesis
• One of the most prolific arenas of drug development
• More than 360 agents in various phases of
development
– Compounds: modeled for direct and/or indirect AA
properties
– Approaches: ligand, receptor, signal, and regulators
– Targets: endothelial cells, tumor cells, pericytes
• Approved: 9 (2 others with indirect effects)
– Most recent Everolimus (3/30/09) in RCC
Ovarian Cancer
Key Signaling Pathways Involved in Ovarian Cancer
Angiogenesis
Yap TA, et al. Nat Cancer Rev 2009; 9:2583; J Clin Oncol, Vol 30, Nº 4, 2012; 441-444
VEGF and Angiopoetin-2 Levels
Markers of Poor Prognosis in Ovarian Cancer
p=0.04
Duncan et al; Clin Cancer Res 2008; 14:3030-3035; Sallinen et al; Int Journal Gyn Oncol; 20; 2010.
Targeting the VEGF Pathway
Strategies
Antibodies to
VEGF
Bevacizumab
Soluble VEGF
receptorsaflibercept
VEGF
VEGFR2
VEGFR tyrosine
kinase
inhibitors:
 Pazopanib
 BIBF1120
Ribozymes
 Cediranib
Migration, permeability, DNA synthesis, survival
Angiogenesis as a Target in Ovarian Cancer:
Anti-VEGF-VEGFR Pathway
• Anti-vascular endothelial growth factor (VEGF) therapy
improves progression-free survival (PFS)
• GOG 218*
Front-line: Bevacizumab
HR = 0.72; 95% CI, 0.63–0.821
• ICON 7*
Front-line: Bevacizumab
HR = 0.81; 95% CI, 0.70–0.942
• AGO-OVAR12
Front-line: Nintedanib
HR = 0.84; 95% CI, 0.72, 0.983
• AGO-OVAR16
Maintenance: Pazopanib
HR = 0.77; 95% CI, 0.64–0.914
• AURELIA**
Platinum-resistant, recurrent / 1 or 2 prior regimens: Bevacizumab
HR = 0.48; 95% CI, 0.38–0.605
• OCEANS*
Platinum-sensitive, recurrent / 1 prior regimen: Bevacizumab
HR = 0.48; 95% CI, 0.41–0.706
Platinum-sensitive, recurrent / 1 prior regimen: Cediranib
HR = 0.57; 95% CI, 0.44–0.747
• ICON6
1.
2.
3.
4.
5.
6.
7.
Burger RA et al. N Engl J Med. 2011;365:2473‒2483.
Perren TJ et al . N Engl J Med. 2011;365:2484‒2496.
du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA5503.
du Bois A et al. LBA ESGO 2013 Liverpool, UK
Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA5002.
Aghajanian C et al. J Clin Oncol. 2012;30:2039‒2045.
Ledermann JA et al . Eur J Cancer. 2013;49(suppl):LBA
*EMA Approved
*FDA Approved
HR = hazard ratio; 95% CI = confidence interval
Single- Agent BEVACIZUMAB in Ovarian Cancer:
Phase II Efficacy Results
Cannistra et al.[1]
(N = 44)
Parameter, %
Garcia et al.2]
(N = 70)
Burger et al.[3]
(N = 62)
GOG#170
Prior regimens
•1
•2
•3
52
48
100
24
66
1o platinum DFI < 6 mos, %
84
40
60
15 mg/kg every
21 days
10mg/kg plus
Ciclophosphamide
50mg/day
15 mg/kg every
21 days
7 (16%)
17(24%)
13(21%)
≥ G3 Proteinuria (%)
0
<16
1
≥ G3 HTA(%)
14
<16
10
Gastrointestinal perforations
(%)
11
6
0
Dose/schedule
RR, n (%)
1. Cannistra SA, et al. J Clin Oncol. 2007;25:5180-5186.
3. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171
2.Garcia AA, et al. J Clin Oncol. 2008;26:76-82.
GOG#218
ICON-7
GOG#218: Schema
Arm
Carboplatin (C) AUC 6
Front-line:
Epithelial OV, PP
or FT cancer
• Stage III optimal
(macroscopic)
• Stage III
suboptimal
• Stage IV
N=1873
Paclitaxel (P) 175 mg/m2
R
A
N
D
O
M
I
Z
E
I
(CP)
Placebo
Carboplatin (C) AUC 6
1:1:1
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
II
(CP + BEV)
Placebo
Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/m2
1ºEnd-Point: PFS
PFS HR0.77
M. PFS shift: 14.0 m  18.2M
N Engl J Med 2011;365:2473-83.,
BEV 15 mg/kg
Cytotoxic
(6 cycles)
Maintenance
(16 cycles)
III
(CP + BEV
 BEV)
15 months
GOG-0218: PFS
RECIST, global clinical deterioration, or CA-1251
Proportion surviving progression free
1.0
0.9
Patients with event, n (%)
0.8
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
423
(67.7)
418
(66.9)
360
(57.8)
10.3
11.2
14.1
Median PFS, months
0.7
Stratified analysis HR
(95% CI)
0.6
One-sided p-value (log rank)
0.908
0.717
(0.759–1.040) (0.625–0.824)
0.080a
<0.0001a
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
N Engl J Med 2011;365:2473-83.
12
24
Months since randomization
ap-value
boundary = 0.0116
36
GOG-0218
CA-125 To Determine Progression
Protocol-defined
PFS analysis
CA-125-censored
PFS analysis
CP (Arm I)
10.3 months
12.0 months
CP + BEV  BEV (Arm III)
14.1 months
18.0 months
3.8 months
6.0 months
0.717
0.645
CP (Arm I)
0
20
CP + BEV  BEV (Arm III)
0
29
Median PFS
Absolute diff. median PFS
Hazard ratio
Censored for CA125, %
Overall survival at time of final
PFS analysis
1.0
0.9
Proportion alive
0.8
0.7
0.6
0.5
0.4
Patients with events, n (%)
0.3
Median (months)
HR (stratified)
(95% CI)
One-sided p-value
1-year OS rate, %
0.2
0.1
Arm I
Arm II
Arm III
CP + PLA → PLA CP + BEV → PLA CP + BEV  BEV
(n=625)
(n=625)
(n=623)
156
150
138
(25)
(24)
(22)
39.3
38.7
39.7
1.036
0.915
(0.827–1.297)
(0.727–1.152)
0.361
0.252
90.6
90.4
91.3
0
0
No. at
risk
625
625
623
N Engl J Med 2011;365:2473-83.,
6
12
442
432
437
18
24
30
36
Months since randomization
173
162
171
46
39
40
42
48
ICON7:
Study design
Carboplatin AUC 6* (C)
Epithelial ovarian,
primary peritoneal or
fallopian tube cancer
● High-risk stage I–IIA
(grade 3 or clear cell)
● Stage IIB–IV
Paclitaxel 175 mg/m2 (P)
R
1:1
n=1528
Carboplatin AUC 6*
Paclitaxel 175 mg/m2 (P)
Bevacizumab 7.5 mg/kg q3w
Stratification variables:
12 months
• Stage I–III debulked ≤1 cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III
• Intent to start treatment ≤/> 4 weeks after surgery
1º End- Point: PFS only determined by RECIST Criteria
HIGH RISK GROUP( 31% ) : FIGO III>1cm/FIGO IV Debulking
Perren TJ et al . N Engl J Med. 2011;365:2484‒2496.
Summary of Updated Results
High risk: FIGO IV or III with >1cm RD
HR 0.68 (95% CI 0.55-0.85)
Median 10.5 vs 15.9mo
HR = 0.81 (95% CI 0.70–0.94)
HR = 0.81 (95% CI 0.63–1.04)
Perren T et al N Engl J Med. 2011 Dec 29;365(26):2484-96.
HR 0.64 (95% CI 0.48-0.85)
Median 36.6 vs 28.8mo
GOG-0218 and ICON7:
Efficacy Across the Trials
GOG-0218
(Arm I vs III)
Results of primary analysis
n
PFS (HR)
Median PFS, months
PFS ∆ , months
p value
1,248
0.72
10.3 vs 14.1
3.8
<0.0001
ICON7
1,528
0.87
17.4 vs 19.8
2.4
0.04
*Censoring CA 125
Results based on RECIST only (regulatory analysis*)
n
PFS (HR)
Median PFS, months
PFS ∆ , months
p value
Subgroup of advanced disease only
(operated FIGO IV/IIIC 1cm+ residuals)
N
PFS (HR)
Median PFS, months
PFS ∆ , months
p value
1,248
0.65
12.0 vs 18.0
6
<0.0001
1,528
0.87
17.4 vs 19.8
2.4
0.04
465
0.68
10.5 vs 15.9
5.4
<0.001
Is the PFS a valid primary end-point?
4th Ovarian Cancer Consensus Conference. June 25 – 27, 2010
UBC Life Sciences Institute, Vancouver, BC
A1-2: What are the appropriate endpoints for different trials: (maintenance, upfront
chemotherapy trials including molecular drugs)
•
The recommended primary endpoints for future front line/maintenance clinical trials in
ovarian cancer are:
• Phase II Screening for activity
• PFS, PFS at defined time point, or Response
• Phase III
• Early ovarian cancer - Recurrence free survival (note: recurrence = recurrent
disease + deaths from any cause)
• Advanced ovarian cancer - Both PFS and OS are important endpoints to understand
the full impact of any new treatment. Although overall survival is an important
endpoint, progression free survival is most often the preferred primary endpoint
for trials because of the confounding effect of the post-recurrence/progression
therapy on overall survival. Each protocol should specify if PFS or OS is the
preferred endpoint. Regardless of which is selected, the study should be designed
and powered for both PFS and OS when feasible.
• Maintenance trials: These criteria should be applied to trials that include
maintenance therapy.
Int J Gynecol Cancer 2011: 21; 756-762
Magnitude of Clinical Benefit:
Is PFS a valid End-Point?

Advanced ovarian cancer has a long survival post-progression and subsequent
interventions can impact on the OS result, especially the crossover.
- In GOG 218, 39% of patients received any anti-angiogenic therapy at relapse1.
- In ICON-7 less than 5% of cross-over could explain the OS

When SPP is long enough( >12 months), the chance of expecting a statistically
significant prolongation of PFS translating into an OS benefit is extremely low and
the number of patients required for demonstrating a survival benefit is extremely
large( >2000)2.

For clinical trials with a PFS benefit, a lack of statistical significance in OS does not
mean a lack of improvement in OS.
1. Chan, et al. SGO 2013: Abstract 292; 2. Broglio et al: J Natl Cancer Inst. 2009 Dec 2;101(23):1642-9
 Bevacizumab, in combination with carboplatin and paclitaxel is
indicated for the front-line treatment of advanced (FIGO
stages III B, III C and IV) epithelial ovarian, fallopian tube, or
primary peritoneal cancer
 Bevacizumab is administered in addition to carboplatin and
paclitaxel for up to 6 cycles of treatment followed by continued
use of Bevacizumab as single agent until disease progression or
for a maximum of 15 months or until unacceptable toxicity,
whichever occurs earlier
 The recommended dose of Bevacizumab is 15 mg/kg of body
weight given once every 3 weeks as an intravenous infusion
GOG 252:
Stage II/III Disease: Small Volume Residual
• Epithelial Ovarian Cancer
• Optimal Stage III
No prior therapy
I
II
• Phase III
• PFS primary endpoint
Open: 27 Jul 2009
Closed: 30 Nov 2011
Accrual: 1100
Study Chair: J Walker
III
Carboplatin AUC=6 (IV)
Paclitaxel 80 mg/m2 (d1, 8, 15 3h)
Bevacizumab (C2+ C22) x 21 days
Carboplatin AUC=6 (IP)
Paclitaxel 80 mg/m2 (d1, 8, 15 3h)
Bevacizumab (C2+ C22) x 21 days
Cisplatin 75 mg/m2 (IP d2)
Paclitaxel 135 mg/m2 (d1, 3h)
Paclitaxel 60 mg/m2 (d8, IP)
Bevacizumab (C2+ C22) x 21 days
ClinicalTrials.gov Identifier: NCT00951496
AGO-OVAR 16: Study Design
N=940
Du Bois A. et al ; Journal Clin Oncol ; 2014.57.4574
HR= 0.77; (95% CI, 0.64 to 0.91)
17.9m
12.3m
Du Bois A. et al ; Journal Clin Oncol ; 2014.57.4574
HR=1.08; 95% CI, 0.87 to 1.33; P.499
Du Bois A. et al ; Journal Clin Oncol ; 2014.57.4574
Recommended Guidelines of Systemic therapy
in Relapsed Ovarian Cancer
/Cediranib/AMG386
OCEANS: Study schema
Platinum-sensitive
recurrent OCa
C AUC 4
CG + PL
G 1000 mg/m2, d1 & 8
•Measurable disease
•ECOG 0/1
•No prior chemo for
recurrent OC
PL q3w until progression
CG for 6 (up to 10) cycles
C AUC 4
•No prior BV
(n=484)
G 1000 mg/m2, d1 & 8
CG + BV
BV 15 mg/kg q3w until progression
CG + PL
(n=242)
CG + BV
(n=242)
Events, n (%)
187 (77)
151 (62)
Median PFS, months
(95% CI)
8.4
(8.3–9.7)
12.4
(11.4–12.7)
Stratified analysis HR
(95% CI)
Log-rank p-value
Aghajanian et al. J Clin Oncol; Vol 30;17;2012
0.484
(0.388–0.605)
<0.0001
28
AURELIA trial design & PFS Results
Platinum-resistant OCa
• ≤2 prior anticancer regimens
• No history of bowel
obstruction/abdominal fistula,
or clinical/ radiological
evidence of rectosigmoid
involvement
Chemotherapy
Treat to
PD/toxicity
Optional BEV
monotherapyc
BEV 15 mg/kg q3wb
+ chemotherapy
Treat to
PD/toxicity
Investigator’s
choice
(without BEV)
R
1:1
ICON 6
Cediranib with Platinum-based Chemotherapy in platinumsensitive relapsed ovarian cancer
Relapse > 6 months after
completion of first line
platinum-based chemotherapy
Cediranib: Tirosin Kinase Inhbitor of
VEGFR1,2,3
Randomise
2:3:3
N=456 pts
6 Cycles platinum-based
Chemotherapy
 Carboplatin/paclitaxel
 Carboplatin/Gemcitabine
 Single agent platinum
Maintenance phase
Arm A
(Chemo only)
Arm B (Concurrent)
Arm C (Maintenance)
Chemotherapy + placebo
Chemotherapy + cediranib
Chemotherapy + cediranib
Continue
placebo
Switch to
placebo
Maintenance cediranib
Treatment continued to 18 months or until
progression (>18 for patients continuing to benefit
Ledermann et al ECCO2013
Overall survival
Maintenance
1.00
Restricted mean survival time increases by
2.7 months with maintenance treatment
(over two years)
Chemotherapy
0.75
Chemo.
Maint.
OS events, n (%)
63 (53.3)
75 (45.7)
Median, months
20.3
26.3
0.50
0.25
Log-rank test
p=0.042
HR (95% CI)
0.70 (0.51 – 0.99)
Test for non-proportionality p=0.0042
0.00
Restricted means, months
0
6
17.6
20.3
12
18
24
30
46
89
27
48
11
22
Months
.
Chemo. 118
Maint. 164
106
159
89
139
Ledermann et al ECCO2013
AMG386
Recurrent EOC
•≤ 3 prior anticancer
regimens
•Evaluable or
measurable disease
R
•GOG Performance
Status of 0 or 1
1:1
•PFI < 12 months
Weekly Paclitaxel
+
Placebo
Treat to
PD/toxicity
Weekly Paclitaxel
+
Trebananib
Treat to
PD/toxicity
Stratification factors
46% of patients w ILP>6Months
•Platinum-free interval (PFI) (≤ 6 vs. > 6 months)
•Measurable disease (Yes/No)
•Region (North America, Western Europe/Australia, Rest of World)
25% 3 previous lines of therapy.
Lancet Oncol, 2014 Jul;15(8), 799-808
TRINOVA- 1 : Progression-free Survival
Events, n (%)
Median PFS, months
Pac + Placebo
(n = 458)
Pac + Trebananib
(n = 461)
361 (79)
310 (67)
5.4
7.2
HR = 0.66 (95% CI, 0.57–0.77)
P (stratified log rank) < 0.001
Monk BJ et al; Lancet Oncol, 2014 Jul;15(8), 799-808
TRINOVA-1: Overall Survival
(Interim Analysis)
Events, n (%)
Median OS, months
Pac + Placebo
(n = 458)
Pac + Trebananib
(n = 461)
163 (36)
150 (33)
17.3
19.0
HR = 0.86 (95% CI, 0.69–1.08)
P (stratified log rank) = 0.19
Monk BJ et al; Lancet Oncol, 2014 Jul;15(8), 799-808
Vanucizumab: RO5520985: A2V CrossMab
(Anti-human VEGF-A &Anti-human/murine Ang-2)
Molecular characteristics
Anti-VEGF-A
Anti-Ang-2
Bevacizumab
LC06
Ang-2
VEGF-A
VH
VH
VL
CH1
DATA
VL AT ASCO 2015
CL
CH2
CH3
Knobs- into- Holes
Crossmab technology allows dual binding capabilities
ClinicalTrials.gov Identifier:NCT01688206
Cervical Cancer
Angiogenesis In Cervical Cancer
• Accumulating evidence supports the concept that angiogenesis plays a
central role in cervical carcinogenesis and disease progression
Atypical vessels on colposcopy
CD31 – Intratumoral microvessel density
Tewari KS, Monk BJ. Invasive Cervical Cancer. In: Clinical Gynecologic Oncology, 8th ed. DiSaia PJ, Creasman WT (eds). Mosby, 2012.
GOG #227-C:
Bevacizumab in the treatment of Recurrent/Metastatic
Cervical Cancer
Warrant phase III: GOG#240
Monk BJ et al Gynecol Oncol 2008;108:21S abstr 45
GOG #240: Incorporation of Bevacizumab in the treatment of
Recurrent and Metastatic Cervical Cancer
Schema
Activated: 4/6/09
Closed to accrual: 1/3/12
1:1:1:1
Paclitaxel 135 or 175 mg/m2 IV
I
Cisplatin 50 mg/m2 IV
Chemo alone
Carcinoma of the cervix
•Primary stage IVB
•Recurrent/persistent
•Measureable disease
•GOG PS 0–1
•No prior chemotherapy for
recurrence
(N=452)
R
A
N
D
O
M
I
Z
E
Stratification factors:
• Stage IVB vs recurrent/persistent
disease
• Performance status
• Prior cisplatin Rx as radiation-sensitizer
1º End-Points:
If adding BEV to Chemo improves OS
If a non-platinum doublet improves OS
Paclitaxel 135 or 175 mg/m2 IV
II
Cisplatin 50 mg/m2 IV
Bevacizumab 15 mg/kg IV
Q21d Rx to
PD, toxicity,
CR
Paclitaxel 175 mg/m2 IV
III
Topotecan 0.75 mg/m2 d1-3
Chemo + Bev
Paclitaxel 175 mg/m2 IV
IV
Topotecan 0.75 mg/m2 d1-3
Bevacizumab 15 mg/kg IV
www.ClinicalTrials.gov Identifier: NCT00803062
GOG #240:
OS for Chemo vs Chemo + Bev
1.0
Events, n (%)
0.9
Median OS,
mos
Chemotherapy
(n=225)
Chemotherapy +
Bev (n=227)
140 (62)
131 (58)
13.3
17.0
Proportion Surviving
0.8
HR=0.71 (97% CI, 0.54-0.94)
P=0.0035
0.7
Median follow-up
0.6
20.8 mos
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
Months on Study
Tewari KS, et al. N Engl J Med 2014;370:734-43
36
GOG #240:
PFS for Chemo vs Chemo + Bev
Events, n (%)
1.0
Median PFS, mos
Proportion Progression-Free
0.9
Chemotherapy
(n=225)
Chemotherapy
+ Bev (n=227)
184 (82)
183 (81)
5.9
8.2
HR=0.67 (95% CI, 0.54-0.82)
2-sided P=0.0002
0.8
RR, %
0.7
36 (CR, n=14)
48 (CR, n=28)
2-sided P=0.00807
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
Months on Study
Tewari KS, et al. N Engl J Med 2014;370:734-43
36
GOG 240:
Chemotherapy in Advanced Cervical Cancer
Phase III Studies
24
Median Overall Survival in Months
CTX vs. CTX BEV
Months
*
13.3 vs. 17.0
p< 0.05
CIS/TOP vs.CIS/PAC
10.3 vs. 12.9
*
CIS vs.CIS/TOP
12
CIS50 vs.CIS100
CIS vs.CIS/IFO
7.0 vs. 7.1
8.0 vs. 8.3
1985
1997
6.5 vs. 9.4
*
0
Courtesy of: Gottfried Konecny MD
2005
2009
2013
FDA News : For Immediate Release
August 14, 2014
FDA approves Bevacizumab to treat patients with aggressive
and late-stage cervical cancer
First targeted agent licensed for gynecologic malignancy in the USA
Endometrial Cancer



Phase II Randomized
1º End-Point: PFS
N= 349
GOG#0086P
 Eligibility:
• Stage III or IVA EC
measurable disease
• Stage IVB or Recurrent EC
(whether there is
measurable disease or not)
• No prior Chemotherapy
Arm 1:
Paclitaxel 175 mg/m2 IV over 3 hours day 1
Carboplatin AUC = 6 IV day 1
Bevacizumab 15mg/kg IV day 1
Maintenance regimen - Bevacizumab 15mg/kg IV every 21 days until disease
progression or prohibition of further therapy.
Arm 2:
Paclitaxel 175 mg/m2 IV over 3 hours day 1
Carboplatin AUC = 5 IV day 1
Temsirolimus 25 mg IV days 1 and 8
Maintenance regimen – Temsirolimus 25 mg IV weekly. Days 1,8
and 15 until disease progression or prohibition of further therapy.
Arm 3:
Ixabepilone 30 mg/m2 IV over 1 hour day 1
Carboplatin AUC = 6 IV day 1
Bevacizumab 15mg/kg IV day
Maintenance regimen - Bevacizumab 15mg/kg IV every 21 days
until disease progression or prohibition of further therapy.
PI: Carol Aghajanian, M.D.
From: 9/14/2009 to 9/9/2014
ClinicalTrials.gov Identifier:NCT00977574
Anti-Angiogenic Therapy in GYNT:
Conclusions
• There is a strong rationale.
• Four clinical trials incorporating BEV in first line and recurrence :
• Level 1 evidence( EMA Approved)
• Meaningful differences in PFS
• OS benefit in ICON-7 High-Risk group
• Pazopanib Trial has a poor therapeutic index( benefit/toxicity)
• Trinova- 1 trial met its 1º End-Point: PFS
• Results from GOG240 have led to a new standard of care in Metastatic/
Recurrent Cervical Cancer
Antiangiogenic Therapy is here to stay.
GRACIAS POR SU ATENCION