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Indicaties Neoadjuvante Chemotherapie: Van Standaard tot Experimenteel

Indicaties Neoadjuvante Chemotherapie: Van Standaard tot Experimenteel. ‘Zegen of mode ?’. Effect of Adjuvant Therap y in Breast Cancer [ Average Results in P atients with sta ges I, II, IIIa tumor s below 7 1 years of age ]. Adj. RT reduces mortality by 10%

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Indicaties Neoadjuvante Chemotherapie: Van Standaard tot Experimenteel

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

  2. Effect of Adjuvant Therapyin Breast Cancer[Average Results in Patients with stages I, II, IIIa tumorsbelow 71 years of age] • 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 Consequently: • The mortality of early breast cancerdecreases by 50% as a result of (optimal) adjuvant therapy R. Peto, 5th EBCTCG meeting, Oxford Sept 2000

  3. Maximum death rate in • Europe around 1990 despite • Increasing incidence • Decrease caused by: • Earlier diagnosis • Adjuvant therapy Lung cancer

  4. Preoperative Chemotherapy • Standard of Care in LABC • Two Large Randomized Trials: • NSABP B-18 (1988, N=1523) • EORTC 10902 (1991, N=698) • 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.

  5. Randomized Studies ofPre- versus Post-operative Chemotherapy

  6. NSABP-18 4 x AC SURGERY N=1523 Rand RT & Follow Up SURGERY 4 x AC Lumpectomy Rate (Proposed, Performed) IBTR, locoregional control RFS, OS Predictive value of Path findings for survival

  7. NSABP-18: Findings at 9 yearsWolmark N, et al. J Natl Cancer Inst Monogr 30: 96, 2001 • No differences in OS or DFS • Lumpectomies: • Pre-operative group 67% • Post-operative group 60% • But: 175% more in T3 tumors • IBTR only after lumpectomy • Pre-operative group 10.7% • Post-operative group 7.6% • Interaction between treatment effect and age (< 50 RFS/OS benefit, > 50 worse)

  8. NSABP B-18, 9 years FU J Natl Cancer Inst Monogr, 30: 96-102, 2001

  9. NSABP B-18, 9 years FU J Natl Cancer Inst Monogr, 30: 96-102, 2001

  10. EORTC 10902 4 x FE60C SURGERY N=698 Rand RT & Follow Up 4 x FE60C SURGERY (1st: < 36 hours of surgery) Lumpectomy Rate Locoregional control RFS, OS

  11. EORTC 10902 - Preoperative Chemotherapy in Operable BCVan der Hage JA, van de Velde CJH et al, J Clin Oncol 19: 4224, 2001 • Preoperative chemotherapy • 246 MRMs were planned, 57 of these were converted to BCT • 77 BCTs were planned; 14 of these were converted to MRM • Only 49% OR (B18: 80%) and 7% pCR (B18: 10%); low anthracyclin-dose ?

  12. EORTC 10902, FU=56 months, locoregional control Van der Hage JG et al, J Clin Oncol 19: 4224, 2001

  13. EORTC 10902, RFS, FU=56 months Van der Hage JG et al, J Clin Oncol 19: 4224, 2001

  14. Preoperative Chemotherapy • Standard of Care in LABC • Optional in operable BC • 2003: Expert Recommendations. J Clin Oncol 21: 2600 • Problems: • Preoperative regimens from randomized studies are currently regarded as inadequate for high-risk disease • Nodal status not available for stratification

  15. 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

  16. 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

  17. 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

  18. 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

  19. Neoadjuvant Chemotherapy in Breast Cancer: Significantly Enhanced Response With Docetaxel Smith IC, et al. J Clin Oncol 20: 1456, 2002

  20. Aberdeen Locally Advanced Breast Cancer Study: Neo-adjuvant taxane improves pCR-rate N=145 RANDOMIZE CVAP x 8 15% pCR LABC CVAP x 4; Doc x 4 31% pCR

  21. 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

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

  23. #502 Hanneman: Patroon voor/na chemotherapie • if there is residual tumour after chemotherapy: hybridization on a microarray as well • correlation of the microarray data with the tumour response to chemotherapy

  24. Unsupervised hierarchical clustering • all biopsies and tumours • both chemotherapies • similar results analyzing AC and AD arm apart 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 B – biopsy T – tumour SD/S – stable disease P – progression

  25. Classifier AC treatment 45 genes Classifier AD treatment 17 genes overlap: 2 genes • most of the genes: • specific for the different drug combinations Classifier to distinguishtreated from untreated samples • classifier consist of • 30 genes (AC + AD) • 45 genes (AC) • 17 genes (AD)

  26. . . . Eindconclusies • Voorlopig blijven pre-operatieve en post-operatieve 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

  27. #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 • 600 Cyclo + 60 Adria versus • 75 Docetaxel + 50 adria • 363 rand. Patients in 25 centers, UK & Belgium

  28. #521 AD vd AC up-front: geen verschil en niet indrukwekkend

  29. #520 Buzdar: Trastuzumab en pCR rate bij HER2/neu+ LABC • 42 patientes single-institution (MD-Anderson) met LABC • 164 patientes gepland, maar monitoring commissie heeft studie gesloten wegens asymmetrisch effect: • 25% pCR in conventionele arm • 67% pCR in Trastuzumab arm (p=0.016)

  30. #520 Buzdar: Trastuzumab en pCR rate bij HER2/neu+ LABC N=42 N=19 RANDOMIZE 4 x Paclitaxel 225/24h q3wk, 4 x FE75C q 3 wk 25% pCR HER+ T1-3 N0-1 Local Therapy N=23 4 x Paclitaxel 225/24h q3wk + weekly (12x) Trastuzumab, 4 x FE75C q 3 wk + weekly (12x) Trastuzumab 67% pCR

  31. #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

  32. #511 (Comella): Weekly PET vs 3-weekly ET in LABC N=175 N=86 RANDOMIZE CDDP 30 Epidadria 50/m q1wk x12 Paclitaxel 120/m + G-CSF pCR: 28% LABC T4 And/or N3 Local Therapy N=89 Epiadria 90/m q 3wk Paclitaxel 175/m x 4 pCR: 17%

  33. #513 late-breaking Moebus (Duits): Dose-dense ECT superior to conventional 1284 RANDOMIZE Epi 150/m Paclitaxel 225/m q2wkx3 Cyclo 2,5 g/m +G-CSF High- risk operable Raar design 3 dingen anders Tussen armen “interim analyse” Epi 90 mg/m q3wkx4 Cyclo 600 mg/m

  34. Conclusions Preoperative Regimens • 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 ? • Survival effects still inevaluable (NSABP B-27 should answer this)

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