Download 1 - Mediterranean School Of Oncology

Ritmi circadiani e qualità di vita: actigrafia e uovi
orizzonti nel carcinoma della mammella
Mediterranean Scholl of Oncology
Endocrinoterapia
adiuvante del
carcinoma nel 2008
Cecilia Nisticò
Dipartimento di Oncologia Medica
Oncologia Medica C
Direttore: Prof. E. Terzoli
IRE - Istituto Nazionale Tumori
Regina Elena
Roma
Roma, 28 Novembre 2008
Breast Cancer Treatment
•
Final Outcomes:
•
Adjuvant setting

•
Treatment Goal: to Cure
Advanced Disease

Treatment Goal: to Care
Adjuvant Therapy
- Early Breast Cancer -
• Chemotherapy
• Endocrine therapy
• Biologic targeted therapy
• Bisphosphonates
–Organ specific therapy
Recent decrease in UK and USA breast
cancer mortality at ages 3569 years
Adj
CTX
Adj
HT
Screeni
ng
Modified
from Peto et
al. Lancet
355:1822,
2000
13%
18%
12%
15%
25%
30%
!
Benefits from Adjuvant
Systemic Therapy
• It is estimated that
– Optimal chemotherapy would reduce annual odds of
recurrence by about 50%-60%
–Optimal endocrine therapy
would reduce annual odds of
recurrence by about 60%-70%
– Trastuzumab would reduce annual odds of recurrence by
45%-55%
– Zoledronic acid would reduce odds of recurrence by about
36%
• Reductions in odds of mortality are somewhat more
modest because of competing causes of death
Benefits from Adjuvant Systemic
Therapy
• Benefits of endocrine therapy are restricted to
ER +/or PgR+ tumors
– Can we predict response to individual endocrine
agents?
• Optimal endocrine therapy would
reduce annual odds of recurrence by
about 60%-70%
• Sequential administration of chemotherapy
followed by endocrine therapy provides optimal
benefit for the overall group
– Can we identify patients in this group who do not
benefit from the addition of chemotherapy?
Davidson N, ASCO 2007
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
15-Year Reductions in Recurrence and Disease-Specific Mortality
Meta-analysis of 194 randomized trials
Meta-analysis of 144,939 women
Treatment
Comparison
Tamoxifen 5 yrs vs
none, ER-positive
women
Breast Cancer
Recurrence, %
Log Rank
2P
Breast Cancer
Mortality, %
Log Rank
2P
11.8
< .00001
9.2
< .00001
EBCTCG. Lancet. 2005;365:1687-17.
EFFICACY OF ADJUVANT TAM
5 YEARS, ER +/UNKNOWN
Relative reduction in odds of
AGE
RECURRENCE
DEATH
< 50
34%(+6%)
24%(+7%)
50-59
35%(+6%)
20%(+7%)
60-69
50%(+5%)
27%(+5%)
> 70
38%(+18%)
p=.00001
26%(+15%)
p=.00001
EBCTCG, Lancet 2005;365:1687-17
Polychemotherapy versus
tamoxifen-treated ER+
disease, for entry age <50:
5-year probabilities of
recurrence (ER+ includes
12% ER unknown)
Early Breast Cancer Trialists’
Collaborative Group (EBCTCG)
Lancet 2005; 365: 1687–1717
EBCTCG Overview (2005)
Davidson N, ASCO 2007
Davidson N, ASCO 2007
Davidson N, ASCO 2007
Davidson N, ASCO 2007
5 yrs
Davidson N, ASCO 2007
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
15-Year Reductions in Recurrence and Disease-Specific Mortality
Meta-analysis of 194 randomized trials
Meta-analysis of 144,939 women
Treatment
Comparison
Ovarian
ablation or
suppression
vs none
Breast Cancer
Recurrence,
%
Log
Rank 2P
Breast
Cancer
Mortality, %
Log
Rank 2P
4.3
.00001
3.2
.004
EBCTCG. Lancet. 2005;365:1687-17.
EBCTCG. Lancet. 2005;365:1687-1717.
Treatment Comparison
Ovarian ablation or
suppression vs none
Breast Cancer
Recurrence, %
Log Rank 2P
Breast Cancer
Mortality, %
Log Rank 2P
4.3
.00001
3.2
.004
EBCTCG Overview (2005)
Ovarian function suppression (OFS) was accepted as an
alternative where tamoxifen was contraindicated.
Retrospective subset analysis suggests that women younger than 40
years seemed to benefit from the addition of goserelin to CMF.
Retrospective subset analysis suggests that women younger than 40
years seemed to benefit from the addition of goserelin to CAF.
Follow up
ASCO 1999/2003
CAF
( %)
CAF-Z
( %)
CAF-ZT
( %)
P
5/ 9 yrs DFS
54/48
65/55
72/64
Vantaggio
72/61
73/62
79/69
Nessun
Vantaggio
< 40
5/ 9 yrs DFS
 40
J Clin Oncol 2005;23:5973-82
Davidson N, ASCO 2007
1. TAM standard all pts
2. TAM for 5 yrs
3. Chemo + TAM better than whatever
alone
4. OS beneficial in youger pts continuing to
menstruate after chemo or TAM
5. Optimal LHRH duration uncertain
6. AIs in Meno after chemo: caution!
7. No data of AIs + LHRH vs TAM (RCTs
ongoing)
AIs & TAM: mechanism of action
Hormonal Adjuvant Treatment
Strategies in Early Breast Cancer
“Up-Front”
R
Tamoxifen
Aromatase Inhibitors
5 years
“Extended Switch”
R
Tamoxifen
10 years
“Early Switch”
Tamox.
2-3 years
R
Tamoxifen
Arom. Inhibitors
3-2 years
Placebo
Aromatase Inhibitors
RCTs – AIs Adjuvant BC
Strategy
RCTs
Pts
Update
Median
FU
(mo.)
ATAC
6186
Lancet
2006
68
BIG-1-98
4922
JCO 2007
ITA-1
380
ITA-2
IES
OS
ANA
0.87 (0.01)
0.85 (0.7)
51
LET
0.82 (0.007)
0.91 (>0.05)
JCO 2001
61
AGT
NR (0.6)
NR (0.005)
448
Ann Oncol
2006
64
ANA
0.57 (0.005)
0.56 (0.1)
4742
Lancet
2007
56
EXE
0.76 (0.0001)
0.85 (0.08)
ABCSG8/ARN
3224
O
Lancet
2005
28
ANA
0.60 (0.0009)
NR (0.16)
30
LET
0.58 (0.001)
0.82 (0.3)
MA.17
“Late”
Switch
AI
DFS/EFS
Up-Front
“Early”
Switch
Efficacy [HR, p]
5157 JNCI 2005
ABCSG 6a
856
JNCI 2007
60
ANA
0.64 (0.047)
NR
NSABP B-33
1598
SABCS
2006
30
EXE
0.68 (0.07)
1.20 (0.63)
Adjuvant Aromatase
Inhibitors
Study
therapy
f.u. HR
Abs d
ATAC 03
upfront
4
0.82
3%
ITA 04
switch
3
0.36
5.3%
IES 04
switch
2.7 0.68
4.7%
MA17 04
extended
2.5 0.58
5%
ARNO ABCSG 04
BIG 05
switch
upfront
0.6
2.4 0.81
3%
2.6%
Aromatase Inhibitors Adjuvant
Trials. Distant metastases
Study
ATAC Lancet 05
BIG 1-98 NEJM 05
IES NEJM 04
ARNO/ABCSG
ITA JCO 05
MA 17
JNCI 05
Lancet 05
Reduction in
distant metastases
14%
27%
p
.01
.0012
34%
39%
51%
.0004
.0067
.06
40%
.002
ATAC: recurrences* before 2.5 years
(HR+ patients)
25
Patients
20
(%)
HR+
A
T
HR
95% CI
p-value
282
370
0.74
(0.64–0.87)
0.0002
15
‘Arimidex’ (A)
Tamoxifen (T)
10
5
0
0
1
At risk:
A 2618
T 2598
2540
2516
2
3
4
Follow-up time (years)
2448
2398
* Censoring non-BC deaths before recurrence
2355
2304
2268
2189
5
6
2014
1932
830
774
Pre-defined adverse events*: ATAC
Median follow-up 68 months
p<0.0001
Hot flushes
p<0.0001
Vaginal bleeding
p<0.0001
Vaginal discharge
Endometrial cancer
Ischemic cerebrovascular
events
Venous thromboembolic
events
Deep venous
thromboembolic events
p=0.02
Anastrozole
Tamoxifen
p=0.03
p=0.0004
p=0.02
p<0.0001
Joint symptoms
p<0.0001
Total fractures
0
10
20
30
Incidence (%)
* Other Pre-defined AE’s with NO significant differences seen between groups:
Ischemic Cardiovascular Disease, Cataracts, Nausea & Vomiting, Mood Disturbances, Fatigue
ATAC Trialists’ Group. Lancet 2005;365:60-62
40
50
ATAC 100 mo.: SAEs: on and off treatment
(Number – safety population)
On treatment
Serious adverse event Anastrozole Tamoxifen
Treatment-related
Off treatment
Anastrozole Tamoxifen
153
284
49
57
Endometrial cancer
4
12
1
12
Myocardial infarction
34
33
26
28
Cerebrovascular accident
20
34
22
20
Fracture episodes*
375
234
146
143
*A fracture episode comprised one or more fractures on the same day based on adverse events and
serious adverse event reports
Predefined adverse events
at any time on treatment or any severity
Hot flushes
Nausea and vomiting
Fatigue / tiredness (asthenia)
Mood disturbances
Musculo-skeletal disorders
Vaginal bleeding
Vaginal discharge
Ischaemic cardiovascular disease
Ischaemic cerebrovascular event
Venous thromboembolic events
Deep venous thromboembolic events
Cataracts
Carpal tunnel syndrome†
†included
as a non-predefined adverse event of interest
Anastrozole
(N = 3092)
Tamoxifen
(N = 3094)
1102 (35.6)
394 (12.7)
578 (18.7)
599 (19.4)
1104 (35.7)
167 (5.4)
110 (3.6)
130 (4.2)
64 (2.1)
87 (2.8)
48 (1.6)
189 (6.1)
79 (2.5)
1263 (40.8)
358 (12.4)
544 (17.6)
555 (17.9)
915 (29.6)
319 (10.3)
409 (13.2)
106 (3.4)
91 (2.9)
141 (4.6)
75 (2.4)
218 (7.0)
22 (0.7)
Deaths according to treatment group
(ITT population)
No. patients (%)
Cause of death
Anastrozole
(n = 3125)
Tamoxifen
(n = 3116)
Total deaths
629 (20)
624 (20)
Deaths after recurrence
350 (11)
382 (12)
Deaths without recurrence
279 (9)
242 (8)
Cardiovascular
67 (2)
66 (2)
Cerebrovascular
25 (1)
29 (1)
Second primary non-breast cancer
84 (3)
60 (2)
Other
103 (3)
87 (3)
Fracture episode rates throughout the
study
Annual
fracture
episode
rates (%)
4
Anastrozole (A)
Tamoxifen (T)
3
2
1
0
0
1
At risk:
A
2984
T
2976
2
2859
2824
3
4
5
6
7
Time since randomization (years)
2745
2699
2640
2572
2496
2419
2306
2208
2077
2000
8
9
1713
1645
702
659
ATAC 100:
benefits continue and detrimental effects
decline after treatment cessation
Time to recurrence
Patients 30
(%)
Fracture episode rates
Tamoxifen (T)
Anastrozole (A)
25
21.8%
Annual 4
fracture
episode
rates (%)
3
Tamoxifen (T)
Anastrozole (A)
20
15
12.5%
2
17.0%
10
1
9.7%
5
Absolute 2.8%
difference
0
0
1
2
3
4
4.8%
0
5
6
Follow-up time (years)
7
8
9
0
1
2
3
4
5
6
7
8
Time since randomisation (years)
9
BIG 1-98: cumulative incidence of
breast cancer relapse
Proportion 20
failing
(%)
15
5-year difference (L-T) = -3.4% (SE 1.2)
Cuminc p=0.0002
13.6%
Tamoxifen (T)
Letrozole (L)
8.1%
10
10.2%
5
6.2%
0
0
1
2
3
4
Time since randomisation (years)
5
SE = standard error
Thürlimann B et al. The Breast 2005;14:S3, abs S4
BIG 1-98 DFS
by Local Pathological Assessment
0.81
All patients (n=8010)
0.84
ER+ / PgR+ (n=5055)
0.83
ER+ / PgR- (n=1631)
0.72
ER+ / PgR unk (n=1154)
0.5
0.75
Favors L
1.0
1.25
Favors T
Hazard Ratio (L:T)
1.5
“Endometrial events” :
Tamoxifen vs Aromatase
Inhibitor
ATAC
BIG 1
Hysterectomy Endometrial
biopsies
5% vs 1%
7.2% vs 1.9%
Trial Design
Tamoxifen
R
A
N
D
O
M
I
Z
E
* Total women years
5162*
Post
Treatment
Follow-up
Tamoxifen
10335*
5294*
2-3 years study
treatment
2-3 years
Diagnosis
Exemestane
Start of
study
Total 5 years
endocrine therapy
Results-event- and recurrence-free survival
Results-survival
Results-secondary outcomes
Cancer Treatment Reviews (2006) 32, 325– 332
TAM
AIs
Aromatase Inhibitors:
Tox Issues
1.
Bone Fractures
2.
Cardiovascular
Disease
Bone Health: Issues
Protective Effects of TAM
 Steroidal vs Non-Steroidal
 Predictive role of BMD on fracture
 Other fracture risk factors:

Patient’ characteristics
 Bone turnover
 Steroid use (abuse?)


What about bisphosphonates?
Fracture incidence
Incidence of fracture reported in different
adjuvant aromatase inhibitor trials
CV Disease - Background
1. The earliest publications of the RCTs using AIs
provided conflicting results about the supposed
higher risk of ischaemic cardiovascular toxicity
2. The pathogenesis of cardiac damage induced by
AIs is still definitively unclear, while some
pathways seem to be involved1:
• The reduction of circulating estradiol
• The unbalanced lipid metabolism
References: 1Howell JSBMB 2005
Lipid effects
 Increase of:
 Colestherol
 TG
 LpA
 LDL-C
 Decrease
 HDL-C
of:
End-Points

Primary

Cardiovascular Adverse Events Rate (CVAE)


Grade 3-4 as defined by NCIC
Secondary

Thromboembolic Adverse Events Rate (TEAE)

Cerebrovascular Adverse Events Rate (CBVAE)
In order to reduce heterogeneity across AIs, the
analysis has been carried on considering:

all AIs (Overall analysis)

only 3rd generation AIs (CVAE-New)
Cuppone F, Cancer 2008
Selected RCTs
Cuppone F, Cancer 2008
Results – CVAE Rate
(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Results – CVAE Rate
(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Results - CVAE Rate-3rd Generation AIs
(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Results - CVAE Rate-3rd Generation AIs
(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Results – TEAE Rate
(Thromboembolic Adverse Events)
Cuppone F, Cancer 2008
Results – CBVAE Rate
(Cerebrovascular Adverse Events)
Cuppone F, Cancer 2008
‘Trial’ Verdict
• Controversial ‘Motive’ (not clear
background)
• Overestimated risk (0.5%) when AI vs TAM
• No difference AIs vs placebo
• Protective effect of TAM really ‘guilty’
…..free for lack of evidences
Cardio-protective effect of tamoxifen
Metanalysis

32 trials comparing tamoxifen against a control
group (metastatic, adjuvant, and prevention
settings)

12 reported on myocardial infarction death
> 52,000 patients; 66% postmenopausal; mean
age 54.8 yrs; mean treatment duration: 4.3 yrs;
mean FU: 5.6 yrs
 Relative risk ratio for fatal MIs (tamoxifen /
control): 0.62 (95% CI: 0.41-0.93)
 Risk ratio without the Scottish trial: 0.81 (95% CI:
0.48-1.37)

Braithwaite et al JGIM 2003;18:937-47
Myocardial Infarction
Cognitive Function, Fatigue
and Menopausal Symptoms
Adjuvant CT
Control
HSCS*
(impairment)
FACT-F
FACT-ES
FACT-G
16%
31
58
77
4%
46
64
93
0.008
0.0001
0.0001
0.0001
* High Sensitivity Cognitive Screen
N Tchen, JCO 2005
LONG TERM TREATMENT WITH A.I.
POTENTIAL
BENEFIT
POTENTIAL
RISK
SUPERIOR EFFICACY
INCREASED FRACTURE RATE
TREATMENT-INDUCED BMD LOSS
LOSS SEVER LONG TERM EFFECTS
 Endometrial cancer
 Thromboembolism
ARTHROMYALGIA
LIPID DISTURBANCES
FEWER HYSTERECTOMIES
COGNITIVE DISTURBANCES
VASOMOTOR SIDE EFFECTS
Tailoring the treatment on the
basis of the clinical histories?

Which patients should we deny the
advantage linked to AI treatment on the
basis of their characteristics?