Diapositiva 1

Taxanes and
New hormonal agents:
How they work?
Taxanes
Microtubules are highly dynamic cytoskeletal fibres that are composed of tubulin of which are
crucial to mitosis and cell division.
Jordan Nat Rev Cancer 2004
Microtubules functions
•
Cell shape
•
Transport of vesicles
•
Mitochondrial function
•
Cell signalling
•
Cell division and mitosis
Emerging mechanistic scenarios of the effects of taxane-based chemotherapy on
microtubules and androgen receptor signaling.
Mistry S J , and Oh W K Mol Cancer Ther 2013;12:555-566
Abiraterone
acetate
Agarwal Fut Oncol 2010 modified
17 hydroxylase -
17-20 lyase
enzalutamide
Testosterone & AR:
Their role in PC
Logothetis Cancer Disc 2013
Seruga Nat Rev Clin Oncol 2011
ES Antonarakis
Oral presentation June 1, 2014
S Antonarakis Oral presentation June 1, 2014
Azad Poster Highlights sessione May 30, 2014
•
•
ARv7, which lacks the hinge region, did not cosediment with microtubules, unlike ARv567.
Nuclear accumulation and transcriptional
activity of ARv7 was unaffected by taxane
treatment.
chaarted
Sweeney Abs #LBA2 Plenary session June 1, 2014
C. Sweeney Abs #LBA2
Plenary session June 1, 2014
Chemotherapy in hormone-sensitive
PC
•
Issues
–
Rationale
–
Selection criteria
–
Side effects
–
Magnitude of the results
–
Additional data
Sweeney Abs #LBA2 Plenary session June 1, 2014
Selection criteria?
Breast cancer
•
•

Click to edit
the vs
outline
ER/PGR
pos
negtext
format
•
Clinical/biological
Second Outline Level
criteria
(St.Gallen
 Third
Outline Level
guidelines)
Fourth Outline


–
–
–
Level
Ki67
 Fifth Outline
Level
HER2 status
 Sixth Outline
ER status Level
 Seventh
Outline Level
 Eighth
Outline Level
Ninth Outline LevelFare clic
per modificare stili del
•
Prostate
testo dello cancer
schema

Click to edit the outline text
•
DRE
format
•
GS Second Outline Level
•
PSA 

Third Outline Level

Fourth Outline
Level
 Fifth Outline
Level
 Sixth Outline
Level
 Seventh
CHAARTED definition of the risk
•
High volume
–
–
Visceral mets and/or
≥ 4 bone mets (at last 1 beyond pelvis and
vertebral column)
CHAARTED definition of the risk
•
High volume
–
–
Visceral mets and/or
≥ 4 bone mets (at last 1 beyond pelvis
andDiscussant
MJ Morris
Plenary session June 1, 2014
vertebral column)
Side effects
CHAARTED
Anemia
1
Thrombocytopenia
-
Neutropenia
12
Febrile neutropenia
6
Fatigue
4
Side effects
CHAARTED
TAX 327
Anemia
1
5
Thrombocytopenia
-
1
Neutropenia
12
32
Febrile neutropenia
6
3
Fatigue
4
5
•
Will chemo became the new standard for
hormonosensitive PC pts?
–
•
YES (for a quote of pts…waiting more accurate
selection criteria)
Are the presented data enough?
–
NO (additional analyses are needed)
Chemo in
early stages
Neo-adjuvant (surgery)
down
organ
confin
ed
author
year
Drug
GS
PSA
T
#
T
PSA
Pettaway
2000
KET+DOX/VBL+E
+ TAB (duration: 12 wks)
>8
>10
3
33
NR
NR
33
Clark
2001
VP16+E x 21 d/ 4 w x 3
>8
>15
2B-3
18
94
100
Hussain*
2003
DOC/3w + E 280 TID x 3-6
>8
>15
>2b
21
100
Dreicer
2004
DOC w x 6
>8
>15
2b-3
29
Beer
2004
DOC+MITOX w x 4 (phase I)
> 4+3
>15
2c-3a
Konety
2004
Carbo AUC 6 + PCT 180
mg/sqm+ EMP 280 TID +
LHRH-A x 4-6
>8
>20
Febbo
2005
DOC w x 24
>20
4+3
mar
gin mFU
%RFb
83
13
69
31
78
14
88
100
30
(#10)
70
13
71
NR
79
11
50
23
71
21
NR
20/2
1
76
NR
NR
3-4
36
22
100
36
NR
29
55
3
19
89 (
MRI)
58
38
NR
NR
NR
Neo-adjuvant (XRT)
author
year
Drug
GS
PSA
T
#
Ben Josef
2001
VP16+E x 2 XRT +
E
>7
>15
1-2
18
Hussain*
11 XRT
2003
DOC/3w + E 280
TID x 3-6
>8
>15
>2b
21
Zelefsky
2004
VBL+E x 2 XRT +
VBL+E x 1
>8
>20
>3
27
mFU
%RFb
73 (3y DFS)
13
71
(2 HT)
66(5y)
Adjuvant
•
Pilepich [RTOG 81-12] (Am J Clin Oncol 1986)
–
•
XRT (64.8-70.2 Gy) CTX+DOX+CDDP
Schmidt (Eur Urol 1996)
 E 600 mg/sqm/d x 2 years


–
XRT or surgery
CTX 1 g/sqm/3w x 2 years
observation
CALGB 90203
neo
adj
Phase III Study of Radical Prostatectomy Alone Versus Neoadjuvant
Docetaxel in High Risk Localized Prostate Cancer
RTOG 9902
adj
Phase III randomized study of androgen suppression and
radiotherapy with or without subsequent paclitaxel, estramustine,

and etoposide in patients with localized high-risk prostate cancer
SWOG 9921
adj
Adjuvant Androgen Deprivation Versus Mitoxantrone Plus
Prednisone Plus Androgen
Deprivation in Selected High Risk

Prostate Cancer Patients Following Radical Prostatectomy: Phase III
XRP6976J/3501
adj
A Multicenter, Open-Label, Randomized, Phase III Trial Comparing
Immediate Adjuvant HormonalTherapy (ELIGARD®- leuprolide
acetate) in Combination with TAXOTERE® Administered Every Three
Weeks Versus Hormonal Therapy Alone Versus Deferred Therapy
Followed by the Same Therapeutic Options in Patients at High Risk
of Relapse After Radical Prostatectomy

FRE-FNCLCCGETUG-12/0203
neo
adj
Click to edit the outline
text format
Second Outline
Level
Third Outline
Level
Fourth Outline
Level
Phase III randomized study of neoadjuvant releasing factor agonist
therapy and antiandrogen therapy with or without docetaxel and
 Fifth
estramustine in patients with locally advanced
prostate cancer or
with a high risk of relapse
Outline
Level
•
Given the lack of phase III trials, there is
limited data regarding the role of (neo)
adjuvant chemotherapy with or without ADT
prior to RP in localized or locally advanced
prostate cancer
K Fizazi Oral presentation June 1, 2014
K Fizazi Oral presentation June 1, 2014
K Fizazi Oral presentation June 1, 2014
K Fizazi Oral presentation June 1, 2014