indicaties neoadjuvante chemotherapie: van standaard tot experimenteel
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Indicaties Neoadjuvante Indicaties Neoadjuvante Chemotherapie:Chemotherapie:
Van Standaard tot ExperimenteelVan Standaard tot Experimenteel
‘‘Zegen of mode ?’Zegen of mode ?’
Effect Effect of of Adjuvant TherapAdjuvant Therapyy in Breast Cancerin Breast Cancer[[Average Results in PAverage Results in Patients atients withwith sta stages ges I, II, IIIa I, II, IIIa
tumortumorss belowbelow 7 71 years of age1 years of age]]
Adj. RT Adj. RT reduces mortality byreduces mortality by 10% 10% Adj. CT Adj. CT reduces mortality byreduces mortality by 20% 20% Adj. HT Adj. HT reduces mortality byreduces mortality by 30% 30% These 3 effects have essentially These 3 effects have essentially no interactionno interaction::
0.9 (RT) x 0.8 (CT) x 0.7 (HT) = 0.50.9 (RT) x 0.8 (CT) x 0.7 (HT) = 0.5
Consequently:Consequently: The mortality of early breast cancerThe mortality of early breast cancer decreases by decreases by
50% 50% as a result of (optimal) adjuvant therapyas a result of (optimal) adjuvant therapy
R. Peto, 5th EBCTCG meeting, Oxford Sept 2000
Maximum death rate inEurope around 1990 despiteIncreasing incidence
Decrease caused by:-Earlier diagnosis-Adjuvant therapy
Lung cancer
Preoperative ChemotherapyPreoperative Chemotherapy
Standard of Care in LABCStandard of Care in LABC Two Large Randomized Trials:Two Large Randomized Trials:
– NSABP B-18 (1988, N=1523)NSABP B-18 (1988, N=1523)– EORTC 10902 (1991, N=698)EORTC 10902 (1991, N=698)
2003: Expert Recommendations. 2003: Expert Recommendations. J Clin J Clin Oncol 21: 2600Oncol 21: 2600
Can PreOpChemo improve cure rate?Can PreOpChemo improve cure rate?– Earlier eradication of micrometastatic disease Earlier eradication of micrometastatic disease
and guidance by tumor-response, versus delay of and guidance by tumor-response, versus delay of local treatment.local treatment.
Randomized Studies ofRandomized Studies ofPre- versus Post-operative ChemotherapyPre- 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-18NSABP-18
4 x AC SURGERY
4 x ACSURGERY
RT & Follow UpRand
Lumpectomy Rate (Proposed, Performed)IBTR, locoregional controlRFS, OSPredictive value of Path findings for survival
N=1523
NSABP-18: Findings at 9 yearsNSABP-18: Findings at 9 yearsWolmark N, et al. J Natl Cancer Inst Monogr 30: 96, 2001Wolmark N, et al. J Natl Cancer Inst Monogr 30: 96, 2001
No differences in OS or DFSNo differences in OS or DFS Lumpectomies:Lumpectomies:
– Pre-operative group 67%Pre-operative group 67%– Post-operative group 60%Post-operative group 60%– But: 175% more in T3 tumorsBut: 175% more in T3 tumors
IBTR only after lumpectomyIBTR only after lumpectomy– Pre-operative group 10.7%Pre-operative group 10.7%– Post-operative group 7.6%Post-operative group 7.6%
Interaction between treatment effect and age Interaction between treatment effect and age (< 50 RFS/OS benefit, > 50 worse)(< 50 RFS/OS benefit, > 50 worse)
NSABP B-18, 9 years FUNSABP B-18, 9 years FU
J Natl Cancer Inst Monogr, 30: 96-102, 2001
NSABP B-18, 9 years FUNSABP B-18, 9 years FU
J Natl Cancer Inst Monogr, 30: 96-102, 2001
EORTC 10902EORTC 10902
4 x FE60C
SURGERY
4 x FE60C
SURGERY
RT & Follow UpRand
Lumpectomy RateLocoregional controlRFS, OS
(1st: < 36 hours of surgery)
N=698
EORTC 10902 - Preoperative Chemotherapy in EORTC 10902 - Preoperative Chemotherapy in Operable BCOperable BC
Van der Hage JA, van de Velde CJH et al, J Clin Oncol 19: 4224, Van der Hage JA, van de Velde CJH et al, J Clin Oncol 19: 4224, 20012001
Preoperative chemotherapyPreoperative chemotherapy– 246 MRMs were planned, 57 of these 246 MRMs were planned, 57 of these
were converted to BCTwere converted to BCT– 77 BCTs were planned; 14 of these were 77 BCTs were planned; 14 of these were
converted to MRMconverted to MRM Only 49% OR Only 49% OR (B18: 80%)(B18: 80%) and 7% pCR and 7% pCR
(B18: 10%);(B18: 10%); low anthracyclin-dose ? low anthracyclin-dose ?
EORTC 10902, FU=56 months,EORTC 10902, FU=56 months, locoregional control locoregional control
Van der Hage JG et al, J Clin Oncol 19: 4224, 2001
EORTC 10902, EORTC 10902, RFSRFS, FU=56 months, FU=56 months
Van der Hage JG et al, J Clin Oncol 19: 4224, 2001
Preoperative ChemotherapyPreoperative Chemotherapy
Standard of Care in LABCStandard of Care in LABC Optional in operable BCOptional in operable BC
– 2003: Expert Recommendations. 2003: Expert Recommendations. J Clin J Clin Oncol 21: 2600Oncol 21: 2600
Problems:Problems:– Preoperative regimens from randomized Preoperative regimens from randomized
studies are currently regarded as studies are currently regarded as inadequate for high-risk diseaseinadequate for high-risk disease
– Nodal status not available for stratificationNodal status not available for stratification
The Effect on Tumor Response of Adding Sequential The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27 Cyclophosphamide: Preliminary Results From NSABP B-27 Bear HD, et al. J Clin Oncol 21: 2165, 2003Bear HD, et al. J Clin Oncol 21: 2165, 2003
The Effect on Tumor Response of Adding Sequential The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27 Cyclophosphamide: Preliminary Results From NSABP B-27 Bear HD, et al. J Clin Oncol 21: 2165, 2003Bear HD, et al. J Clin Oncol 21: 2165, 2003
The Effect on Tumor Response of Adding Sequential The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27 Cyclophosphamide: Preliminary Results From NSABP B-27 Bear HD, et al. J Clin Oncol 21: 2165, 2003Bear HD, et al. J Clin Oncol 21: 2165, 2003
The Effect on Tumor Response of Adding Sequential The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Preoperative Docetaxel to Preoperative Doxorubicin and
Cyclophosphamide: Preliminary Results From NSABP B-27 Cyclophosphamide: Preliminary Results From NSABP B-27 Bear HD, et al. J Clin Oncol 21: 2165, 2003Bear 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 Aberdeen Locally Advanced Breast Cancer Study: Neo-adjuvant taxane Cancer Study: Neo-adjuvant taxane
improves pCR-rateimproves pCR-rate
RA
ND
OM
IZE
CVAP x 8
CVAP x 4; Doc x 4
LABC
15% pCR
31% pCR
N=145
Conclusies pre-operatieve Conclusies pre-operatieve chemotherapie mammacachemotherapie mammaca
Vaker MST mogelijkVaker MST mogelijk Geen (of weinig) invloed op locale Geen (of weinig) invloed op locale
controle of overlevingcontrole of overleving pCR waarschijnlijk goed surrogaat pCR waarschijnlijk goed surrogaat
eindpunt voor overlevingeindpunt voor overleving Toevoeging Docetaxel (of: Taxaan ?) Toevoeging Docetaxel (of: Taxaan ?)
vergroot kans op pCRvergroot kans op pCR
Preoperative Systemic Therapy – the ChallengePreoperative Systemic Therapy – the Challenge
Kaufmann et al, J Clin Oncol 21: 2600-08, 2003
#502 Hanneman: Patroon voor/na #502 Hanneman: Patroon voor/na chemotherapiechemotherapie
if there is residual tumour after chemotherapy: hybridization on a microarray if there is residual tumour after chemotherapy: hybridization on a microarray as wellas well
correlation of the microarray data with the tumour response to chemotherapycorrelation of the microarray data with the tumour response to chemotherapy
Unsupervised hierarchical Unsupervised hierarchical clusteringclustering
all biopsies and tumoursall biopsies and tumours both chemotherapiesboth chemotherapies
similar results analyzing similar results analyzing AC and AD arm apartAC and AD arm apart
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
B – biopsyT – tumourSD/S – stable
diseaseP – progression
ER pos
ER neg
n.a.
• tumours sensitive to primary CT:– significant changes in gene expression
profile
• resistant tumours: – no major changes in gene expression
profile
Classifier to distinguishClassifier to distinguishtreated from untreated samplestreated from untreated samples
ClassifierAC
treatment
45 genes
ClassifierAD
treatment
17 genes
overlap:2 genes
• most of the genes:
specific for the different drug combinations
• classifier consist of
30 genes (AC + AD)
45 genes (AC)
17 genes (AD)
. . . Eindconclusies. . . Eindconclusies
Voorlopig blijven pre-operatieve en post-Voorlopig blijven pre-operatieve en post-operatieve chemotherapie equivalent als operatieve chemotherapie equivalent als MST geen probleem of geen optie is.MST geen probleem of geen optie is.
Voor LABC is preoperatieve chemotherapie Voor LABC is preoperatieve chemotherapie de standaardde standaard
De ontwikkelingen in de preoperatieve De ontwikkelingen in de preoperatieve chemotherapie komen overeen met de chemotherapie komen overeen met de ontwikkelingen van de postoperatieve ontwikkelingen van de postoperatieve adjuvante chemotherapieadjuvante chemotherapie
#521 AD vd AC up-front: geen #521 AD vd AC up-front: geen verschil en niet indrukwekkendverschil en niet indrukwekkend
Angloceltic group phase IIIAngloceltic group phase III T=3 cm of groterT=3 cm of groter 3-weekly courses x 63-weekly courses x 6
– 600 Cyclo + 60 Adria600 Cyclo + 60 Adria versusversus– 75 Docetaxel + 50 adria75 Docetaxel + 50 adria
363 rand. Patients in 25 centers, UK & 363 rand. Patients in 25 centers, UK & BelgiumBelgium
#521 AD vd AC up-front: geen #521 AD vd AC up-front: geen verschil en niet indrukwekkendverschil en niet indrukwekkend
AD % AC %
cl CR 20 17
cl PR 50 44
cl OR 71 61 p=0.06
pCR 16 15
pCR + i.s. 21 24
pCR + LN- 12 16 NS
#520 Buzdar: Trastuzumab en #520 Buzdar: Trastuzumab en pCR rate bij HER2/neu+ LABCpCR rate bij HER2/neu+ LABC
42 patientes single-institution (MD-42 patientes single-institution (MD-Anderson) met LABCAnderson) met LABC
164 patientes gepland, maar monitoring 164 patientes gepland, maar monitoring commissie heeft studie gesloten wegens commissie heeft studie gesloten wegens asymmetrisch effect:asymmetrisch effect:– 25% pCR in conventionele arm25% pCR in conventionele arm– 67% pCR in Trastuzumab arm (p=0.016)67% pCR in Trastuzumab arm (p=0.016)
#520 Buzdar: Trastuzumab en #520 Buzdar: Trastuzumab en pCR rate bij HER2/neu+ LABCpCR rate bij HER2/neu+ LABC
RA
ND
OM
IZE
4 x Paclitaxel 225/24h q3wk,4 x FE75C q 3 wk
N=42
HER+T1-3N0-1
4 x Paclitaxel 225/24h q3wk + weekly (12x) Trastuzumab,4 x FE75C q 3 wk + weekly (12x) Trastuzumab
N=19
N=23
LocalTherapy
67% pCR
25% pCR
#520 Buzdar: Trastuzumab en #520 Buzdar: Trastuzumab en pCR rate bij HER2/neu+ LABCpCR rate bij HER2/neu+ LABC
Geen klinisch manifeste decomp. cordisGeen klinisch manifeste decomp. cordis Wel > 10% EF daling bij 5 patientes, Wel > 10% EF daling bij 5 patientes,
waarbij in 2 gevallen reversibelwaarbij in 2 gevallen reversibel Nog geen data over RFS en OS benefitNog geen data over RFS en OS benefit 4 andere trials met Trastuzumab en 4 andere trials met Trastuzumab en
gelijktijdige chemotherapie up-front bij gelijktijdige chemotherapie up-front bij HER2/neu+: 18-23% pCRHER2/neu+: 18-23% pCR
#511 (Comella): Weekly PET vs #511 (Comella): Weekly PET vs 3-weekly ET in LABC3-weekly ET in LABC
RA
ND
OM
IZE
CDDP 30Epidadria 50/m q1wk x12Paclitaxel 120/m + G-CSF
N=175
LABCT4And/orN3 Epiadria 90/m q 3wk
Paclitaxel 175/m x 4
N=86
N=89
LocalTherapy
pCR: 28%
pCR: 17%
#513 late-breaking Moebus (Duits): #513 late-breaking Moebus (Duits): Dose-dense ECT superior to Dose-dense ECT superior to
conventionalconventional
RA
ND
OM
IZE
Epi 150/mPaclitaxel 225/m q2wkx3Cyclo 2,5 g/m +G-CSF
Epi 90 mg/m q3wkx4Cyclo 600 mg/m
1284
Raar design3 dingen andersTussen armen
“interim analyse”
High-riskoperable
Conclusions Preoperative Conclusions Preoperative RegimensRegimens
Dose-dense concept confirmedDose-dense concept confirmed Addition of Taxane (Docetaxel) improves Addition of Taxane (Docetaxel) improves
pCR rate (and other response parameters)pCR rate (and other response parameters) However, 6 courses of AC appear equivalent However, 6 courses of AC appear equivalent
to 6 courses of ADto 6 courses of AD– Alkylating agent cyclophosphamide important for Alkylating agent cyclophosphamide important for
subgroup ?subgroup ?– Sequence important ?Sequence important ?
Survival effects still inevaluable (NSABP B-27 Survival effects still inevaluable (NSABP B-27 should answer this)should answer this)
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