Indicaties Neoadjuvante Chemotherapie: Van Standaard tot Experimenteel

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







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)


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


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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Indicaties Neoadjuvante Chemotherapie: Van Standaard tot Experimenteel