Transcript Titel ASCO abstract - Antoni van Leeuwenhoek

Indicaties Neoadjuvante
Chemotherapie:
Van Standaard tot Experimenteel
‘Zegen of mode ?’
Effect of Adjuvant Therapy in Breast Cancer
[Average Results in Patients with stages I, II, IIIa
tumors below 71 years of age]
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Adj. RT reduces mortality by 10%
Adj. CT reduces mortality by 20%
Adj. HT reduces mortality by 30%
These 3 effects have essentially no interaction:
0.9 (RT) x 0.8 (CT) x 0.7 (HT) = 0.5
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Consequently:
The mortality of early breast cancer decreases by
50% as a result of (optimal) adjuvant therapy
R. Peto, 5th EBCTCG meeting, Oxford Sept 2000
Maximum death rate in
Europe around 1990 despite
Increasing incidence
Decrease caused by:
-Earlier diagnosis
-Adjuvant therapy
Lung cancer
Preoperative Chemotherapy
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Standard of Care in LABC
Two Large Randomized Trials:
– NSABP B-18 (1988, N=1523)
– EORTC 10902 (1991, N=698)
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2003: Expert Recommendations. J Clin
Oncol 21: 2600
Can PreOpChemo improve cure rate?
– Earlier eradication of micrometastatic disease
and guidance by tumor-response, versus delay of
local treatment.
Randomized Studies of
Pre- versus Post-operative Chemotherapy
STUDY
N
REGIMEN PRE
SURV
NSABP B-18
1523 AC x 4
NS
Broet
390
CAF x 4
NS
Semiglazov
271
ThioMF 1-2x
0.04
Mauriac
272
EVMMiTVn
NS
Makris
309
MitoxMTX x 4
NS
EORTC 10902
698
FE60C x 4
NS
NSABP-18
N=1523
4 x AC
SURGERY
Rand
RT & Follow Up
SURGERY
4 x AC
Lumpectomy Rate (Proposed, Performed)
IBTR, locoregional control
RFS, OS
Predictive value of Path findings for survival
NSABP-18: Findings at 9 years
Wolmark N, et al. J Natl Cancer Inst Monogr 30: 96, 2001
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No differences in OS or DFS
Lumpectomies:
– Pre-operative group 67%
– Post-operative group 60%
– But: 175% more in T3 tumors
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IBTR only after lumpectomy
– Pre-operative group 10.7%
– Post-operative group 7.6%
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Interaction between treatment effect and age
(< 50 RFS/OS benefit, > 50 worse)
NSABP B-18, 9 years FU
J Natl Cancer Inst Monogr, 30: 96-102, 2001
NSABP B-18, 9 years FU
J Natl Cancer Inst Monogr, 30: 96-102, 2001
EORTC 10902
N=698
4x
FE60C
SURGERY
RT & Follow Up
Rand
SURGERY
4x
FE60C
(1st: < 36 hours of surgery)
Lumpectomy Rate
Locoregional control
RFS, OS
EORTC 10902 - Preoperative Chemotherapy in
Operable BC
Van der Hage JA, van de Velde CJH et al, J Clin Oncol 19: 4224,
2001
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Preoperative chemotherapy
– 246 MRMs were planned, 57 of these
were converted to BCT
– 77 BCTs were planned; 14 of these were
converted to MRM
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Only 49% OR (B18: 80%) and 7% pCR
(B18: 10%); low anthracyclin-dose ?
EORTC 10902, FU=56 months,
locoregional control
Van der Hage JG et al, J Clin Oncol 19: 4224, 2001
EORTC 10902, RFS, FU=56 months
Van der Hage JG et al, J Clin Oncol 19: 4224, 2001
Preoperative Chemotherapy
Standard of Care in LABC
 Optional in operable BC
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– 2003: Expert Recommendations. J Clin
Oncol 21: 2600
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Problems:
– Preoperative regimens from randomized
studies are currently regarded as
inadequate for high-risk disease
– Nodal status not available for
stratification
The Effect on Tumor Response of Adding Sequential
Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27
Bear HD, et al. J Clin Oncol 21: 2165, 2003
The Effect on Tumor Response of Adding Sequential
Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27
Bear HD, et al. J Clin Oncol 21: 2165, 2003
The Effect on Tumor Response of Adding Sequential
Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27
Bear HD, et al. J Clin Oncol 21: 2165, 2003
The Effect on Tumor Response of Adding Sequential
Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27
Bear HD, et al. J Clin Oncol 21: 2165, 2003
Neoadjuvant
Chemotherapy in
Breast Cancer:
Significantly Enhanced
Response With
Docetaxel
Smith IC, et al. J Clin
Oncol 20: 1456, 2002
Aberdeen Locally Advanced Breast
Cancer Study: Neo-adjuvant taxane
improves pCR-rate
N=145
RANDOMIZE
LABC
CVAP x 8
15% pCR
CVAP x 4; Doc x 4
31% pCR
Conclusies pre-operatieve
chemotherapie mammaca
Vaker MST mogelijk
 Geen (of weinig) invloed op locale
controle of overleving
 pCR waarschijnlijk goed surrogaat
eindpunt voor overleving
 Toevoeging Docetaxel (of: Taxaan ?)
vergroot kans op pCR
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Preoperative Systemic Therapy – the Challenge
Kaufmann et al, J Clin Oncol 21: 2600-08, 2003
#502 Hanneman: Patroon voor/na
chemotherapie
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if there is residual tumour after chemotherapy: hybridization on a microarray
as well
correlation of the microarray data with the tumour response to chemotherapy
Unsupervised hierarchical
clustering
B T T B T B B T B T T T T B B T B T B B T T B T B T B B T B B B B B B B T B B B B B B B B B B B B B B B B B B B B B B B B T B T
S D
•
S D
S D
S D
S D
P
P
S
S D S D
all biopsies and
B
– biopsy
tumours
sensitive to primary
CT:
tumours
T
– tumour
 both chemotherapies
– significant changes in gene expression profile
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• resistant
 similar tumours:
results
SD/S
P
– stable disease
– progression
AC and AD
– noanalyzing
major
changes in gene expression profile
arm apart
ER pos
ER neg
n.a.
Classifier to distinguish
treated from untreated samples
• classifier consist of
30 genes (AC + AD)
45 genes (AC)
17 genes (AD)
• most of the genes:
Classifier
AC
treatment
45 genes
Classifier
AD
treatment
17 genes
overlap:
2 genes
specific for the different drug combinations
. . . Eindconclusies
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Voorlopig blijven pre-operatieve en postoperatieve chemotherapie equivalent als
MST geen probleem of geen optie is.
Voor LABC is preoperatieve chemotherapie
de standaard
De ontwikkelingen in de preoperatieve
chemotherapie komen overeen met de
ontwikkelingen van de postoperatieve
adjuvante chemotherapie
#521 AD vd AC up-front: geen
verschil en niet indrukwekkend
Angloceltic group phase III
 T=3 cm of groter
 3-weekly courses x 6
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– 600 Cyclo + 60 Adria
– 75 Docetaxel + 50 adria
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versus
363 rand. Patients in 25 centers, UK &
Belgium
#521 AD vd AC up-front: geen
verschil en niet indrukwekkend
AD % AC %
cl CR
20
17
cl PR
50
44
cl OR
71
61
pCR
16
15
pCR + i.s.
21
24
pCR + LN-
12
16
p=0.06
NS
#520 Buzdar: Trastuzumab en
pCR rate bij HER2/neu+ LABC
42 patientes single-institution (MDAnderson) met LABC
 164 patientes gepland, maar monitoring
commissie heeft studie gesloten wegens
asymmetrisch effect:
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– 25% pCR in conventionele arm
– 67% pCR in Trastuzumab arm (p=0.016)
#520 Buzdar: Trastuzumab en
pCR rate bij HER2/neu+ LABC
N=42
RANDOMIZE
HER+
T1-3
N0-1
N=19
4 x Paclitaxel 225/24h q3wk,
4 x FE75C q 3 wk
N=23
4 x Paclitaxel 225/24h q3wk
+ weekly (12x) Trastuzumab,
4 x FE75C q 3 wk
+ weekly (12x) Trastuzumab
25% pCR
Local
Therapy
67% pCR
#520 Buzdar: Trastuzumab en
pCR rate bij HER2/neu+ LABC
Geen klinisch manifeste decomp. cordis
 Wel > 10% EF daling bij 5 patientes,
waarbij in 2 gevallen reversibel
 Nog geen data over RFS en OS benefit
 4 andere trials met Trastuzumab en
gelijktijdige chemotherapie up-front bij
HER2/neu+: 18-23% pCR
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#511 (Comella): Weekly PET vs
3-weekly ET in LABC
N=175
RANDOMIZE
LABC
T4
And/or
N3
N=86
CDDP 30
Epidadria 50/m q1wk x12
Paclitaxel 120/m + G-CSF
N=89
Epiadria 90/m
Paclitaxel 175/m
pCR: 28%
Local
Therapy
q 3wk
x4
pCR: 17%
#513 late-breaking Moebus (Duits):
Dose-dense ECT superior to
conventional
1284
RANDOMIZE
Highrisk
operable
Epi 150/m
Paclitaxel 225/m q2wkx3
Cyclo 2,5 g/m
+G-CSF
Epi 90 mg/m
q3wkx4
Cyclo 600 mg/m
Raar design
3 dingen anders
Tussen armen
“interim analyse”
Conclusions Preoperative
Regimens
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Dose-dense concept confirmed
Addition of Taxane (Docetaxel) improves
pCR rate (and other response parameters)
However, 6 courses of AC appear equivalent
to 6 courses of AD
– Alkylating agent cyclophosphamide important for
subgroup ?
– Sequence important ?
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Survival effects still inevaluable (NSABP B-27
should answer this)