Indicaties Neoadjuvante Chemotherapie Van Standaard tot Experimenteel Zegen

Indicaties Neoadjuvante Chemotherapie: Van Standaard tot Experimenteel ‘Zegen of mode ? ’

Effect of Adjuvant Therapy in Breast Cancer [Average Results in Patients with stages I, IIIa tumors below 71 years of age] n n 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 n Consequently: The mortality of early breast cancer decreases by 50% as a result of (optimal) adjuvant therapy R. Peto, 5 th 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 n n Standard of Care in LABC Two Large Randomized Trials: – NSABP B-18 (1988, N=1523) – EORTC 10902 (1991, N=698) n n 2003: Expert Recommendations. J Clin Oncol 21: 2600 Can Pre. Op. Chemo 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

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 n n No differences in OS or DFS Lumpectomies: – Pre-operative group 67% – Post-operative group 60% – But: 175% more in T 3 tumors n IBTR only after lumpectomy – Pre-operative group 10. 7% – Post-operative group 7. 6% n 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 4 x FE 60 C SURGERY RT & Follow Up Rand SURGERY 4 x FE 60 C (1 st: < 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 n Preoperative chemotherapy – 246 MRMs were planned, 57 of these were converted to BCT – 77 BCTs were planned; 14 of these were converted to MRM n Only 49% OR (B 18: 80%) and 7% p. CR (B 18: 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 n Optional in operable BC n – 2003: Expert Recommendations. J Clin Oncol 21: 2600 n 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 p. CR-rate N=145 RANDOMIZE LABC CVAP x 8 15% p. CR CVAP x 4; Doc x 4 31% p. CR

Conclusies pre-operatieve chemotherapie mammaca Vaker MST mogelijk n Geen (of weinig) invloed op locale controle of overleving n p. CR waarschijnlijk goed surrogaat eindpunt voor overleving n Toevoeging Docetaxel (of: Taxaan ? ) vergroot kans op p. CR n

Preoperative Systemic Therapy – the Challenge Kaufmann et al, J Clin Oncol 21: 2600 -08, 2003

#502 Hanneman: Patroon voor/na chemotherapie n n 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 • all biopsies and B – biopsy tumours sensitive to primary CT: tumours T – tumour n both chemotherapies – significant changes in gene expression profile n • resistant n 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 n n n 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 n T=3 cm of groter n 3 -weekly courses x 6 n – 600 Cyclo + 60 Adria – 75 Docetaxel + 50 adria n versus 363 rand. Patients in 25 centers, UK & Belgium

#521 AD vd AC up-front: geen verschil en niet indrukwekkend

#520 Buzdar: Trastuzumab en p. CR rate bij HER 2/neu+ LABC 42 patientes single-institution (MDAnderson) met LABC n 164 patientes gepland, maar monitoring commissie heeft studie gesloten wegens asymmetrisch effect: n – 25% p. CR in conventionele arm – 67% p. CR in Trastuzumab arm (p=0. 016)

#520 Buzdar: Trastuzumab en p. CR rate bij HER 2/neu+ LABC N=42 RANDOMIZE HER+ T 1 -3 N 0 -1 N=19 4 x Paclitaxel 225/24 h q 3 wk, 4 x FE 75 C q 3 wk N=23 4 x Paclitaxel 225/24 h q 3 wk + weekly (12 x) Trastuzumab, 4 x FE 75 C q 3 wk + weekly (12 x) Trastuzumab 25% p. CR Local Therapy 67% p. CR

#520 Buzdar: Trastuzumab en p. CR rate bij HER 2/neu+ LABC Geen klinisch manifeste decomp. cordis n Wel > 10% EF daling bij 5 patientes, waarbij in 2 gevallen reversibel n Nog geen data over RFS en OS benefit n 4 andere trials met Trastuzumab en gelijktijdige chemotherapie up-front bij HER 2/neu+: 18 -23% p. CR n

#511 (Comella): Weekly PET vs 3 -weekly ET in LABC N=175 RANDOMIZE LABC T 4 And/or N 3 N=86 CDDP 30 Epidadria 50/m q 1 wk x 12 Paclitaxel 120/m + G-CSF N=89 Epiadria 90/m Paclitaxel 175/m q 3 wk x 4 p. CR: 28% Local Therapy p. CR: 17%

#513 late-breaking Moebus (Duits): Dose-dense ECT superior to conventional 1284 RANDOMIZE Highrisk operable Epi 150/m Paclitaxel 225/m q 2 wkx 3 Cyclo 2, 5 g/m +G-CSF Epi 90 mg/m q 3 wkx 4 Cyclo 600 mg/m Raar design 3 dingen anders Tussen armen “interim analyse”

Conclusions Preoperative Regimens n n n Dose-dense concept confirmed Addition of Taxane (Docetaxel) improves p. CR 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 ? n Survival effects still inevaluable (NSABP B-27 should answer this)