Transcript Tratamiento del carcinoma escamoso de esófago

V Reunión Nacional de Avances en Cáncer de Próstata
Neoadyuvancia y Adyuvancia con
Hormonoterapia y Quimioterapia en la
Enfermedad Localizada y Localmente
Avanzada
Albert Font
Servicio de Oncología Médica
Institut Català d´Oncologia
Hospital Germans Trias i Pujol, Badalona
Guadalajara, 18 de junio del 2009
Treatment of localized and locally-advanced
prostate cancer according to risk groups
Pisansky et al. NEJM 2006
Relative Risk of Prostate Cancer-Specific Mortality
according to Treatment and Risk Group
Two multi-institutional databases including 7316 patients
Risk Group
RR
Surgery
95% CI
Low
1.0
Intermediate
4.9
1.7-8.1
High
14.2
5.0-23.4
P
RR
Radiotherapy
95% CI
P
1.0
.003
5.6
2.0-9.3
.0012
<.0001 14.3
5.2-24.0
<.0001
D´Amico et al. J Clin Oncol 2003;21:2163-2172
Prostate cancer as a systemic disease (I)
Prognostic impact of CK+ prostate cancer cells in bone
marrow before prostatectomy
Weckermann D, et al. J Clin Oncol 2009;27:1549
Prostate cancer as a systemic disease (II)
Cell-free tumor DNA and circulating tumor cells in blood
plasma in prostate cancer
Schwarzenbach H, et al. Clin Cancer Res 2009;15:1032
Is there a role for chemotherapy in high-risk
localized prostate cancer ?
• Prostate cancer is a systemic disease even in early stages
• Pretreatment clinical factors such as Gleason score, PSA levels
and clinical stage can select patients with high risk of PSA
recurrence and prostate cancer-related death (D´Amico, 2003)
• Treatment options for men with high-risk localized prostate cancer
remain inadequate
• Chemotherapy is effective in advanced hormone-refractory
prostate cancer
• Hormonal therapy followed by prostatectomy has not improved
long-term outcomes in high-risk patients treated in the
neoadjuvant setting
Summary of neoadjuvant hormonal therapy trials
with > 100 patients enrolled
Gomella LG et al. Urology 2003;62(supp6B):46
Adjuvant chemotherapy in high-risk localized
prostate cancer
Study
No pts
Schmidt, 1996
184
Regimen
Cyclophosphamide vs
Surgery
Results
Yes
No difference in OS
ADT + Mitox ( 4 c) vs ADT Yes
Improvement with
Mitox
EMP vs Observation
Wang, 2000
96
Trials with Docetaxel
Rosenbaum, 2005 77
Srinivas, 2006
20
Docetaxel wkly (6 months)
Yes
Docetaxel wkly (6 months) Surgery/RT
EMP: Estramustine ADT: Androgen deprivation therapy Mitox: Mitoxantrone
PFS: 15.7 m
Well tolerated
SWOG 9921: Hormonal therapy vs hormonal
therapy plus chemotherapy after prostatectomy
High Risk Localized
Prostate Cancer after
Radical
Prostatectomy
(n=1360 p)
R
A
N
D
O
M
I
Z
E
Hormonal Therapy ( 2 years)
Hormonal Therapy (2 years) plus
+ mitoxantrone/prednisone
Primary Endpoint: Overall Survival
Status: Closed
(6 cycles)
Veteran Affairs CSP 553 study:
Adjuvant chemotherapy in high-risk localized
prostate cancer
High Risk Localized
Prostate Cancer after
Prostatectomy
(pT3b or T4, pT3a+Gleason > 7,
PSA > 20 ng/ml or risk of PSA
progression > 50% )
Post-RP: PSA < 0.1
(n= 636 p)
R
A
N
D
O
M
I
Z
E
Docetaxel (75 mg/m2 every 3
weeks) + prednisone
( 6 cycles)
Observation
Primary Endpoint: Progression-free survival
Study start: June 2006
Hormonal and radiation therapy or hormonal and
radiation therapy followed by docetaxel:
RTOG 0521 study
High Risk Prostate
Cancer:
• Gleason 7-8/PSA 20-150
•Gleason 8/PSA < 20/T2-4
•Gleason>9/ PSA< 150
R
A
N
D
O
M
I
Z
E
ADT ( 8 weeks) RT (72-75 Gy) +
ADT (20 months)
ADT ( 8 weeks) RT (72-75 Gy) +
Docetaxel ( 6 cycles)+ ADT (20 m)
N= 600 p
Primary Endpoint: Survival at 4 years
Start Date: December 2005
Rationale for neoadjuvant treatment of prostate
cancer
Neoadjuvant trials in high-risk localized
prostate cancer
• Non-docetaxel based chemotherapy with/without
hormonal therapy
• Docetaxel-based chemotherapy without hormonal
therapy
• Docetaxel-based chemotherapy with hormonal
therapy
•
Ongoing phase III trials
• Trials with new targeted therapies
Phase II trials of non-docetaxel-based
chemotherapy (I)
No.
Pts
Regimen
Van Poppel,
1995
29
Estramustine
0
41%
NR
52%
Pettaway, 2000
30
KAVE
0
67%
37%
17%
16
Estramustine/
VP-16
0
56%
13%
13%
Study
Clark, 2001
Pathological Results
pCR
ECE
LN
SM+
Konety, 2004
35
Taxol/estramustine/
carboplatin
0
53%
5%
22%
Ko, 2006
12
Taxol/
estramustine
0
NR
8%
25%
ECE: extracapsular extension LN: Lymph nodes SM+: Surgical margins involved
Phase II trials of docetaxel-based
chemotherapy without hormonal therapy (II)
Study
No. Pts
Dreicer, 2004
29
Febbo, 2005
16
22
Garzotto, 2006
Friedman, 2008
15
Regimen
Docetaxel (wkly)
Pathological Results
pCR
ECE
LN
MR+
0
49%
14%
50%
Docetaxel (wkly)
0
62%
0%
NR
Docetaxel/
Mitoxantrone
0
34%
29%
34%
0
56%
13%
40%
Docetaxel/
capecitabine
Phase II trials of docetaxel-based chemotherapy
with hormonal therapy (III)
Study
Pathological Results
pCR
ECE
LN
MR+
No. Pts
Regimen
21
Docetaxel/
Estramustine
0
70%
10%
30%
29
Docetaxel (wkly)
0
82%
14%
39%
22
Docetaxel/
Estramustine
0
36%
23%
27%
Chi, 2008
72
Docetaxel (wkly)
3%
44%
6%
27%
Mellado, 2009
57
Docetaxel (wkly)
6%
47%
4%
35%
Hussain, 2003
Magi-Galluzzi,
2007
Sella, 2008
Phase II trials of docetaxel-based chemotherapy
with hormonal therapy
Study
Pathological Results
pCR
ECE
LN
MR+
No. Pts
Regimen
21
Docetaxel/
Estramustine
0
70%
10%
30%
29
Docetaxel (wkly)
0
82%
14%
39%
22
Docetaxel/
Estramustine
0
36%
23%
27%
Chi, 2008
72
Docetaxel (wkly)
3%
44%
6%
27%
Mellado, 2009
57
Docetaxel (wkly)
6%
47%
4%
35%
Hussain, 2003
Magi-Galluzzi,
2007
Sella, 2008
Docetaxel-based chemotherapy with hormonal
therapy in high-risk localized prostate cancer (I)
Chi et al , 2008
Regimen
Docetaxel (wkly) plus
ADT
Mellado et al, 2009
Docetaxel (wkly) plus
ADT
Treatment
Duration
6 months
3 months
No of patients
72
57
Risk Factors
1
2
3
41 (65%)
19 (30%)
3 (5%)
33 (58%)
21 (36%)
3 (5%)
Median follow-up
42 months
35 months
Docetaxel-based chemotherapy with hormonal
therapy in high-risk localized prostate cancer (II)
Chi et al , 2008
Mellado et al, 2009
Surgical Margins +
17 (27%)
18 (35%)
Extracapsular extension
28 (44%)
24 (47%)
Lymph nodes involved
4 (6%)
2 (4%)
pCR
2 (3%)
3 (6%)
Pathological Response
Significant PR (*)
26%
16 (25%)
10 (18%)
19 (30%)
18 (31%)
Outcome
Biochemical relapse
BFS in p with significant PR
89%
(*) Significant PR: <5%-10% tumor or less by volume in prostatectomy
Neoadjuvant hormonal and radiation therapy
with/without docetaxel in high-risk prostate
cancer: Dana-Farber Institute study
High Risk Prostate
Cancer:
• T1b-2a + PSA> 10 or
Gleason >7
•T2c-T4
R
A
N
D
O
M
I
Z
E
ADT ( 6 months ) + Docetaxel x 3
cycles followed by RT (70 Gy) +
Docetaxel (20 mg/m2/wkly)
ADT ( 6 months ) + RT (70 Gy)
N= 350 p
Primary Endpoint: Overall survival
Start Date: June 2005
Neoadjuvant docetaxel and hormonal therapy vs
prostatectomy alone in high-risk localized prostate
cancer: CALGB 90203 study
High Risk
Prostate Cancer:
• Biochemical PFS <
60% by Kattan
nomogram
•PSA < 100 ng/ml
•Clinical stage: T1-3a
R
A
N
D
O
M
I
Z
E
Prostatectomy
Docetaxel ( 6 cycles)
+ ADT (18-24 weeks)
Prostatectomy
N= 750 p
Primary Endpoint: Biochemical progression free survival at 3 years
Start Date: December 2006
Genetic markers involved in prostate cancer
biology
Potential for new targeted therapies
Efstathiou et al. Clin Cancer Res 2007
Why may new therapies be explored in highrisk localized prostate cancer?
High-risk localized
Advanced hormone-refractory
Primary
endpoint
Pathological
response
Biochemical-progresion free survival,
overall survival
No of patients
required
Low
High
Follow-up
Short
Long
Tumor tissue
available
Yes
Not usually
Predictive
genetic markers
Yes
More difficult
Impact of new targeted therapies as neoadjuvant
therapy for high-risk prostate cancer
Study
Vuky J, et al.
Cancer 2009
Mathew P, et al.
J Urol 2009
Regimen
Docetaxel (wkly)/gefitinib
(31p)
Docetaxel (wkly)/imatinib
(36p)
Docetaxel/bevacizumab
Oh W.K, et al
(41 p)
Proc ASCO 2009
Results









PSA responses: 21 p (68%)
Extracapsular extension: 13 p (43%)
Positive SM: 11 p (33%)
No pT0 was observed
Extracapsular extension: 22 p (65%)
Positive SM: 6 p (18%)
No pT0 was observed
Partial responses by erMRI: 36% p
No pathological results
•Median decline in tumor volume was 46%
•36% of patients had a partial response by erMRI
•9 p (22%) had a PSA declines > 50%
Ongoing trials with new targeted therapies
as neoadjuvant treament in high-risk
localized prostate cancer (I)
Institution
U. British
Columbia
Hoosier
Oncology
Group
M.D Anderson
Regimen
No. pts
Endpoint
OGX-011
45 p
Pathological complete
response
Dasatinib
39 p
Pathological complete
response
Sunitinib
42 p
Tumor response
Ongoing trials with new targeted therapies
as neoadjuvant treament in high-risk
localized prostate cancer (II)
Institution
Fred
Hutchinson
Cancer
Research
Center
NCI
Sidney Kimmel
Comprehensive
Cancer Center
MSKCC
Regimen
No. pts
Endpoint
Sorafenib
20 p
Molecular studies
(transcript profiles)
Everolimus
30 p
Pathological complete
responses
Sirolimus
60 p
Pharmacogenetic
studies
Vorinostat
38 p
Pathological complete
responses
Genetic markers to predict eficacy of
neoadjuvant therapies
Role of BRCA 1
Kennedy RD, et al. JNCI 2004;96:1659-68
Reconstitution of wild-type BRCA1 results in sensitivity
to antimicrotubule agents paclitaxel and vinorelbine in
BRCA1 mutant HCC1937 cell line
Dose
Response
Curves for HCCBR1 and HCCEV
Re sponse Curv e(1000x)
s for HCCBR116 and HCCEV1
with
Taxol
(A)Dose
(B)
PACLITAXEL
VINORELBINE
(10000x)
100
90
HCCEV1
80
80
70
70
% Control
% Control
90
100
HCCBR116
HCCBR11660
IC5072h :7.73x10-9M
50 72hrs : 6.21x10-6M
HCCEV1 IC50
60
50
40
40
30
30
20
20
10
10
HCCBR116
HCCEV1
0
10 -10 10 -9 10 -8 10 -7 10 -6 10 -5 10 -4 10 -3
0
10 -1110 -1010 -910 -810 -710 -610 -510 -410 -3
M olarity of Taxol
M olarity of Vinore lbine
HCCBR116: IC50 = 7.73 x 10 –9M
HCCEV1: IC50 = 6.21 x 10 –6M
HCCBR116: IC70 = 1.9 x 10 –9M
HCCEV1: IC70 = 1.7 x 10 –5M
(A) Dose inhibition curves comparing the IC50-70 values of (A) Paclitaxel and (B) Vinorelbine in the
BRCA1 mutant HCC1937 cells reconstituted with exogenous wild type BRCA1 (HCCBR116) compared to
HCC1937 cells reconstituted with empty vector (HCCEV1). In each case the HCCBR116 cells display a
marked increase in sensitivity to these antimicrotubule agents compared to the HCCEV1 cells.
Quinn et al. Cancer Res 2003
siRNA of BRCA1 led to paclitaxel and docetaxel resistance, and reconstitution of
BRCA1 enhanced sensitivity to paclitaxel and vinorelbine
Abrogation of BRCA1 increases sensitivity to cisplatin and resistance to paclitaxel
Quinn et al. Clin Cancer Res 2007
BRCA1 mRNA expression predict survival in
ovarian cancer patients treated with chemotherapy
Quinn JE, et al. Clin Cancer Res 2007;13:7413-20
BRCA1 expression in prostate cancer
BRCA1 – a predictive marker of response to docetaxel-based
chemotherapy in prostate cancer
Schayek H, et al. Clin Cancer Res 2009;15: 1558
Conclusions
• Several phase II trials have confirmed the safety and
feasibility of neoadjuvant chemotherapy followed by
prostatectomy in high-risk localized prostate cancer
• A significant percentage of patients can attain a significant
pathological response after neoadjuvant chemotherapy –
associated with better prognosis
• High-risk patients may be optimal candidates for testing the
activity of new therapies in the neoadjuvant setting
• The analysis of predictive and prognostic genetics markers
should be included in these studies.
• Close collaboration between urologists, medical oncologists
and radiotherapists is required to develop multimodal
strategies.
What can we do to improve?
We need new strategies in
translational research and clinical
trials in prostate cancer. We can
learn a lesson from investigation in
NSCLC or breast cancer