Chemotherapie beim primären Mammakarzinom

Präsentation zum Thema: "Chemotherapie beim primären Mammakarzinom"—  Präsentation transkript:

1 Chemotherapie beim primären Mammakarzinom
Heinz Kölbl Brustzentrum Mainz

2 Fisher et al, Ann Surg 168: , 1968

3 CMF – effektiv auch nach 30 Jahren
n = 386 N+ 12 x CMF vs. nihil 30-Jahres follow-up HR 0,71 HR 0,79 +7% +9% Bonadonna et al, N Engl J Med 294: , 1976 Bonadonna et al, N Engl J Med 332: , 1995 Bonadonna et al, BMJ 330: 217, 2005

4 Chemotherapie bei jeder Patientin?

5 St. Gallen Risikoeinteilung
Risikokategorie niedrig Nodal-negativ und Vorliegen aller u.g. Faktoren pT1 G I >/= 35 J. ER u/o PR positiv Keine extensive Angioinvasion HER-2 negativ intermediär Nodal-negativ und Nichterfüllen mindestens eines der u.g. Faktoren 1-3 Lymphknoten und ER u/o PR positiv und HER-2 negativ hoch 1-3 Lymphknoten und ER/PR negativ u/o HER-2 positiv > 3 Lymphknoten Goldhirsch et al, Ann Oncol 18: , 2007

6 Adjuvant! Ravdin et al, J Clin Oncol 19: , 2001

7 Prognosealgorithmen -Sensitivität und Spezifität
Metastasis or death within 5 years (49/377) within 10 years (71/251) Prognostic factors Sensitivity Specificity St. Gallen 2007 94% 20% 93% 15% Adjuvant! 92% 19% NNBC 84% 41% 85% 33% Schmidt et al, Ann Oncol, 2008 [epub ahead of print]

8 Chemotherapie vs nihil prämenopausal
+12,5% +4,7% EBCTCG, Lancet 365: , 2005

9 Chemotherapie vs nihil postmenopausal
+6% +2,6% EBCTCG, Lancet 365: , 2005

10 EBCTCG Metaanalyse Anthrazykline vs CMF
Anthrazykline sind nur in Dreierkombinationen (z.B. FEC) effektiver als CMF EBCTCG, Lancet 365: , 2005

11 Oxford LoE: 1a GR: A AGO:++
Anthracyclines Oxford LoE: 1a GR: A AGO:++ Are superior to CMF (EBCTCG 2007) Showed benefit in single studies only for: 3-drug combination: FE100Cx6 / CE120Fx6 / FA60Cx6 or sequence: E100x4/Ax4CMFx4 but not for two-drug combinations: ACx4 (= CMFx6) or E100Cx8 (= CMFx6) The superiority of an anthracycline-containing adjuvant combination schedule is based on the data of the metaanalysis (EBCTCG 2005). The benefit of anthracycline-based combination therapy has been shown in single studies only for the triple combination (Coombes 1996, Levine 1998, Mouridsen 1999) or sequential anthracycline-CMF-combinations (Gennari 2006). The efficacy of the two-drug combination AC respectively EC is not greater than the standard CMF schedule (Fisher 1990, Fisher 2000, Piccart 2001). In addition, the efficacy of the two-drug combination can not be enhanced through increasing the number of cycles or the dosage (Piccart 2001, Henderson 2003). Four or eight cycles of E60C are regarded as being underdosed and less effective than CMF. Four or eight cycles of E100C are considered as being similar effective as CMF (Piccart 2001, Azambuja 2006). References: Azambuja E, J Clin Oncol 24(suppl): 19s, 2006 (abstr 568) Coombes RC, J Clin Oncol 14: 35, 1996 Early Breast Cancer Trialists' Collaborative Group. Lancet 365: 1687, 2005 Fisher B, J Clin Oncol. 8: 1483, 1990 Fisher B, Proc Am Soc Clin Oncol 19: 72, 2000 (abstr 277) Gennari A, J Clin Oncol 24(suppl): 20s, 2006 (abstr 569) Henderson IC, J Clin Oncol 21: Hutchins L, J Clin Oncol 23: 8313, 2006 Levine MN, J Clin Oncol 16: 2651, 1998 Mouridsen H, Proc Am Soc Clin Oncol 18: 68, 1999 (abstr 254) Piccart MJ, J Clin Oncol 19: 3103, 2001

12 FEC / FAC Optimal combination and dosage
Oxford / AGO LoE / GR Dosage Epirubicin  30 mg/m²/week 1b A ++ Doxorubicin = 20 mg/m²/week 1b A ++ Regimen French: FE100C q3w x 6 1b B ++ Canadian: Cp.o.E60F d1+8 q4w x 6 1b B + UK: E100 q3w x 4 - CMF x 4 1b B + US: FA60C q3w x 6 1b B + The adequate dosage of doxorubicin is 20 mg/m2/week, a dose reduction decreases the efficacy (Wood 1994, Hutchins 2006) and an increase of the dose does not result in an improvement (Henderson 2003). The needed threshold dose for epirubicin is 30 mg/m2/week and should not drop below (French Adjuvant Study Group 2000, Levine 2001). Six cycles of an anthracycline-containing combination therapy are superior compared to a shortened therapy (Wood 1994, Fumoleau 1999). Therefore, six cycles of FA60C q3w (Wood 1994), six cycles of Cp.o.E60F d1+8 q4w („Canadian FEC“, Levine 2001) or four cycles of E100 q3w in a sequential schedule followed by four cycles of CMF d1+8 q4w (Poole 2006) are regarded as adequate regimen. Due to the extrapolation of the comparison of different study data, six cycles of FE100C q3w („French FEC“, French Adjuvant Study Group 2000) seem to be equieffective. Including the long term-toxicity of the „Canadian FEC“ regime, the „French FEC“ protocol is therefore a feasible alternative. The standard dosage of cyclophosphamide is 600 mg/m2 q3w in the anthracycline-based combination, the reduction to 500 mg/m2 („French FEC“) seems to be feasible without disadvantage, and the increase of the cumulative dosage or dose intensity does not reveal a benefit (Fisher 1997, Fisher 1999). Cyclophosphamide is given at a dose of 600 mg/m2 d1+8 q4w intravenously in the CMF-combinations, alternatively the classical oral application with 100 mg/m2 d1-14 q4w can be used. References French Adjuvant Study Group, J Clin Oncol 19: 602, 2000 Fisher B, J Clin Oncol 15: 1858, 1997 Fisher B, J Clin Oncol 17: 3374, 1999 Fumoleau P, Proc Am Soc Clin Oncol 18: 67, 1999 (abstr 252) Henderson IC, J Clin Oncol 21: Hutchins L, J Clin Oncol 23: 8313, 2006 Levine MN, J Clin Oncol 19: 599, 2001 Poole CJ, N Engl J Med 355: 1920, 2006 Wood WC, N Engl J Med 330: 1253, 1994

13 Müssen es immer Anthrazykline sein?

14 Docetaxel / Cyclophosphamid
+3% +6% HR 0,67 HR 0,76 ns n = 1016, 4 x AC vs 4 x DC Jones et al, J Clin Oncol 24: , 2006

15 Non-anthracycline containing regimens
Oxford / AGO LoE / GR Equivalent OS efficacy to 4 x A/EC: CMF 1a A + Superior OS efficacy to 4 x AC: DC 1b B HER-2 positive disease: D/Carbo/Trastuzumab 2b B + The efficacy of CMF has been shown in numerous single studies with a long term follow up of meanwhile up to 20 years and has been proven in metaanalyses (Bonadonna 1995, EBCTCG 2005). Therefore, six cycles of CMF can be given in patients with contraindications for anthracycline-containing regimens (Fisher 1990, Piccart 2001). If under the consideration of the risks (cardiac toxicity, secondary leukaemia) the potential additional benefit of an anthracycline-based combination therapy is regarded as too low, an anthracycline-free combination can be chosen (Jones 2006, Jones 2007, Slamon 2006). References: Bonadonna G, N Engl J Med 332: 901, 1995 Early Breast Cancer Trialists' Collaborative Group. Lancet 365: 1687, 2005 Fisher B, J Clin Oncol 8: 1483, 1990 Piccart MJ, J Clin Oncol 19: 3103, 2001 Jones SE, J Clin Oncol 24: 5381, 2006 Jones S, Breast Cancer Res Treat 106 (suppl 1): S5, 2007 (abstr 12) Slamon D, Breast Cancer Res Treat 100 (suppl 1), 2006 (abstr) D=Docetaxel; C=Cyclophosphamide

16 CALGB 9344 +5% HR 0,83 +3% HR 0,82 n = 3121 N+ AC vs. AC – Paclitaxel
5-Jahres follow-up 6% Hypersensitivität 18% Parästhesien HR 0,83 +3% HR 0,82 Henderson et al, J Clin Oncol 21: , 2003

17 PACS 01 +5% HR 0,82 +4% HR 0,73 n = 1999 N+ FEC vs. FEC-Docetaxel
5-Jahres follow-up 11.2% febrile Neutropenie 10.3% Nagelveränderungen 4.8% Ödeme 4.0% Stomatitis HR 0,82 +4% HR 0,73 Roche et al, J Clin Oncol 24: , 2006

18 Metaanalyse Taxane adjuvant
+ 5% - 13 randomisierte Studien Patientinnen - Überlebensdaten favorisieren Taxane gilt für alle untersuchten Subgruppen HR 0,85 + 3% HR 0,83 De Laurentiis et al, J Clin Oncol 26: 44-53, 2008

19 Welches Taxan und wie eingesetzt?

20 E1199 weekly Paclitaxel +4,6% HR 1,27 +3,2% HR 1,32
Sparano et al. N Engl J Med 358: , 2008

21 Rationale der dosisdichten Chemotherapie
1012 108 104 100 Eine dosisdichte Chemotherapie führt gegenüber der Standardtherapie theoretisch: zu geringeren Wachstumsintervallen des Tumors zur schnellerem Abfall des Tumorvolumens zur effektiveren Abtötung von Tumorzellen Anzahl der Zellen Zeit C Hudis et al.: SABCS 2005, oral presentation # 41

22 AGO-Studie ETC vs. EC  T Zeit bis zum Rezidiv
1.0 ETC 5-Jahres DFS: 70% 0.8 0.6 Rate ohne Progress EC  T 5-Jahres DFS: 62% 0.4 +8% Log-Rang-Test: p = 0,00079, zweiseitig 0.2 ETC: n = 641, 182 Ereignisse EC  T: n = 611, 226 Ereignisse 0.0 Monate 10 20 30 40 50 60 70 80 90 Verbleibende Pat. „at risk“ ETC EC ->T Möbus VJ.: SABCS 2006, oral presentation # 43

23 AGO-Studie ETC vs. EC  T Gesamtüberleben
1.0 ETC 5-Jahres Gesamtüberleben: 82% 0.8 EC  T 5-Jahres Gesamtüberleben: 77% 0.6 Gesamtüberlebensrate +5% 0.4 Log-Rang-Test: p = 0,029, zweiseitig 0.2 ETC: n = 641, 114 Ereignisse EC  T: n = 611, 139 Ereignisse 0.0 Monate 10 20 30 40 50 60 70 80 90 Verbleibende Pat. „at risk“ ETC EC  T Möbus VJ.: SABCS 2006, oral presentation # 43

24 Adjuvant chemotherapy (dose-dense and/or dose-escalated) in node-positive disease
Oxford / AGO LoE / GR Dose-dense regimen (N +) dd ACP/AC-P q2w (instead of q3w) (CALGB 9741) 1b B +*° AC/ddP q1w x 12 (instead of p q3w) 1b B + Dose-dense and dose-escalated regimen (N  4+) dd E-P-C q2w (instead of EC-P q3w) (AGO) 1b B +*° High-dose regimen (N  10+) high-dose/AST (instead of Cx w/o AST) 1a A - * Dose-dense regimen are defined as chemotherapy schedules in which the intervals between the cycles can be shortened to a minimum (in general from three weeks to two weeks) due to the administration of granulocyte-colony stimulating substances. The principle of dose-dense schedules has been discussed for a long time (especially Skipper 1964, Goldie 1979, Frei 1980, Bonadonna 1981, Hryniuk 1986, Norton 1988). The data of the CALGB 9741 study have demonstrated for the first time in the clinical setting that the administration of a dose-dense regime can achieve a relevant benefit in patients with nodal-positive breast cancer. Because of the short follow up period these data can not be considered as a basis for general recommendations (Citron 2003). Dose-dense and intensive chemotherapy schedules improve the relapse-free and overall survival compared to conventional adjuvant chemotherapy treatment plans independent of the hormonal receptor status in patients with  4 lymph nodes (Moebus 2006). High-dose chemotherapy regimen followed by autologous stem cell transplantation should only be used in the context of well-designed clinical trials (Berry 2007) References: Berry DA, Breast Cancer Res Treat 106 (suppl 1): S5, 2007 (abstr 11) Bonadonna G, N Engl J Med 304:10, 1981 Citron ML, J Clin Oncol 21:1431, 2003 Frei E 3d, Am J Med 69:585, 1980 Goldie JH, Cancer Treat Rep 63:1727, 1979 Hryniuk W, J Clin Oncol 4:1162, 1986 Moebus V, Breast Cancer Res Treat 100 (suppl 1): S20, 2006 (abstr 43) Norton L. A Cancer Res 48: 7067, 1988 Skipper HE, Cancer Chemother Rep 35:1, 1964 P = Paclitaxel *Study participation recommended °treatment in experienced centers

25 Auf einen Blick …

26 Adjuvant chemotherapy
Oxford / AGO LoE / GR Anthracyclines (instead of CMF) 1a A ++ Taxanes (node-positive disease) 1a A ++ Taxanes (node-negative disease) 2b B +/-* Dose-dense (node-positive disease) 1b B +* CMF (instead of no therapy) 1a A ++ If the indication for an adjvuvant chemotherapy is given after a risk/benefit evaluation, anthracycline-based combination chemotherapy is regarded as standard treatment. As shown in a metaanalysis, this regimen induces an additional benefit with a reduction of the relapse rate (ratio 0.89, p=0.0001) and mortality (ratio 0.84, p<0.001) compared with adjuvant CMF-therapy after 15 years (EBCTCG 2005). The superiority of an anthracycline-based triple combination (CEF, FEC, FAC) versus CMF has been shown in single studies (Coombes 1996, Levine 1998, Mouridsen 1999). In the treatment of nodal-positive disease, taxane-containing regimen improve the relapse-free survival (Mamounas 2005, Martin 2005a) as well as the overall survival (Henderson 2003, Martin 2005b, Roche 2006, Bria 2006) compared to taxane-free options. Sequential therapy with docetaxel at standard dose seems to be superior compared to docetaxel in combination with the anthracycline in reduced dosage (Crown 2006). Dose-dense (q2w) adjuvant chemotherapeutic schedules improve the relapse-free and overall survival compared to conventional adjuvant treatment options (Citron 2003). However, as shown in a retrospective subgroup analysis, this applies only for ER-negative disease (Hudis 2005). Dose-dense and dose-intensive chemotherapeutic options improve the relapse-free and overall survival compared to conventional chemotherapy independent of the hormonal receptor status when at least four lymph nodes are involved (Moebus 2006). CMF should be given at a dosage of C 600 mg/m2 d1+8 q4w i.v., alternatively the classical oral application can be chosen with C 100 mg/m m2 d1-14 p.o. q4w. The three-weekly administration implies an underdosing, because a dose of CMF less than 85 % of the conventional dosage leads to a reduction of the efficacy (Bonadonna 1995). Similar conclusions can be drawn from the data of a study in the metastatic setting (Engelmann 1991) and in an older metaanalysis (Hryniuk 1986). Therefore, CMF at a dosage of 600/40/600 mg/m2 q3w is regarded as not adequate. References: Bria E, Cancer 106: 2337, 2006 Bonadonna G, N Engl J Med 332:901, 1995 Citron ML, J Clin Oncol 21: 1431, 2003 Coombes RC, J Clin Oncol 14: 35, 1996 Crown et al. J Clin Oncol 24 (suppl): 7s, 2006 (abstr LBA519) Early Breast Cancer Trialists' Collaborative Group. Lancet 365: 1687, 2005 Engelsman E, Eur J Cancer 27:966, 1991 Henderson IC, J Clin Oncol 21: Hryniuk W, J Clin Oncol 4:1162, 1986 Hudis C, Breast Cancer Res Treat 94 (suppl 1): S20, 2005 (abstr 41) Levine MN, J Clin Oncol 16: 2651, 1998 Mamounas EP, J Clin Oncol 23: 3686, 2005 Martin M, Breast Cancer Res Treat 94 (suppl 1): S20, 2005a (abstr 39) Martin M, N Engl J Med 352: 2302, 2005b Moebus V, Breast Cancer Res Treat 100 (suppl 1): S20, 2006 (abstr 43) Mouridsen H, Proc Am Soc Clin Oncol 18: 68, 1999 (abstr 254) Roche H. J Clin Oncol 24: 5664, 2006 intravenous day 1+8 q28d x 6 DI: 86% oralCyclo d1-14 day 1+8 q28d x 6 DI: 100% * Study participation recommended

27 Neoadjuvante Chemotherapie

28 NSABP B-18 Überleben Fisher et al, J Natl Cancer Inst Monogr: , 2001

29 NSABP B-18 Bedeutung der pCR
+12% +17% Fisher et al, J Natl Cancer Inst Monogr: , 2001

30 Primary systemic chemotherapy Indications
Oxford / AGO LoE / GR Inoperable breast cancer 1c A ++ Inflammatory breast cancer 1b B ++ If similar postoperative adjuvant chemotherapy is indicated 1b A + * Primary systemic therapy (PST) is indicated in inoperable and inflammatory breast cancer, but also increasingly in operable breast cancer with tumor diameters of at least 2 centimeters.1-5 PST is a valid treatment option, if mastectomy seems necessary, but patient wishes breast conservation.6-17 Adjuvant chemotherapy is usually indicated in hormone receptor negative breast cancer. In those tumors the patholgical complete response rate following PST is significantly higher than in hormone receptor positive breast cancer.18 Patients may choose to receive systemic therapy before surgery to take advantage of the response assessment of the primary tumor as tumor response to PST is a surrogate for evaluating the effect of chemotherapy on micrometastases Furthermore, a demonstrable response to PST may have a positive effect on patients compliance. PST may also be advisable for patients who wish to delay surgery, eg. in the second or third trimester of pregnancy.22 References 1. Hortobagyi G, et al. in Bonadonna G, Hortobagyi GN, Gianni AM (eds): Textbook of Breast Cancer: A Clinical Guide to Therapy. London, UK, Martin Dunitz Ltd, 1997, pp 2. Kaufmann M, et al. J Clin Oncol 21, 2600, 2003 3. Schwartz FG, et al. Cancer 100, 2512, 2004 4. Mano MS, et al. Ann Oncol 15, 1161, 2004 5. Hutcheon AW, et al. Am Soc Clin Oncol, Educational Book, 40th Annual Meeting, June 5-8, 2004, New Orleans, LA, pp 6. Bonadonna G, et al. J Natl Cancer Inst 82, 1539, 1990 7. Jacquillat C, et al. Cancer 66, 119, 1990 8. Anderson ED, et al. Eur J Cancer 29A, 1796, 1993 9. Calais G, et al. Cancer 74, 1283, 1994 10. Scholl SM, et al. Eur J Cancer 30A, 645, 1994 11. Smith IE, et al. J Clin Oncol 13, 424, 1995 12. Chollet P, et al. Eur J Cancer 33, 862, 1997 13. Fisher B, et al. J Clin Oncol 15, 2483, 1997 14. Bonadonna G, et al. J Clin Oncol 16, 93, 1998 15. Fisher B, et al. J Clin Oncol 16, 2672, 1998 16. Van der Hage JA, et al. J Clin Oncol 19, 4224, 2001 17. Gianni L, et al. Proc Am Soc Clin Oncol 21, 34a, 2002 (abstr 132) 18. Bear, et al. J Clin Oncol 21, 4165, 2003 19. von Minckwitz G, et al. Proc Am Soc Clin Oncol 21, 43a, 2002 (abstr 168) 20. Hutcheon AW, et al. Breast Cancer Res Treat 82 (Suppl 1), S9, 2003 (abstr 11) 21. Bear HD, et al. Breast Cancer Res Treat 88 (suppl 1), S16, 2004 (abstr 26) 22. Berry DL, et al. J Clin Oncol 17, 855, 1999 * Study participation recommended

31 Darauf aufbauend…

32 Primary systemic therapy Procedures in case of insufficient response
Oxford / AGO LoE / GR In case of stable disease: Completion of PST, followed by surgery 5 D ++ Continuation of PST with non cross-resistant regimen 2b B + AC X 4  D X 4 2b B + DAC X 2  NX x 4 2b B +/- In case of progressive disease: Stop of PST and immediate surgery or radiotherapy 4 D ++* Additional adjuvant chemotherapy with non cross resistant regimen 4 D +/- In case of poor response to primary systemic therapy (PST) alternative strategies should be discussed, ie immediate surgery or continuation of PST with a non cross-resistant chemotherapy regimen.1-6 In case of progressive disease immediate surgery or primary radiotherapy is recommended. References 1. Kayat D, et al. Am Soc Clin Oncol, Educational Book, 37th Annual Meeting, May 12-15, 2001, San Francisco, CA, pp 2. Smith IC, et al. J Clin Oncol 20, 1456, 2002 3. Bear, et al. J Clin Oncol 21, 4165, 2003 4. Hutcheon AW, et al. Breast Cancer Res Treat 82 (suppl 1), S9, 2003 (abstr 11) 5. Bear HD, et al. Breast Cancer Res Treat 88 (suppl 1), S16, 2004 (abstr 26) 6. von Minckwitz G, et al. SABCS 2005 (Abstr 38) * Study participation recommended

33 Primary systemic therapy Timing of surgery and radiotherapy
Oxford / AGO LoE / GR Surgery 4 C ++ After leucocyte nadir (2 to 4 weeks after last course of chemotherapy) Radiotherapy after mastectomy 2b B ++ 2-3 weeks after surgery Indications according to stage of disease before PST (cN+, cT3/4a-d) It is unknown wether preoperative radiotherapy following primary systemic therapy (PST) achieved similar results as radiotherapy following PST and surgery. Preoperative radiotherapy might result in higher rates of breast conservation without compromising cosmetic result.1 However, preoperative external beam and brachytherapy are not established as modes of treatment in conjunction with PST2 and do not replace adequate surgery3-6 which should be performed after leucocyte nadir around 2 to 4 weeks following last cycle of chemotherapy.7 Adjuvant radiotherapy after PST should be administered according to the same recommendations made for those patients who do not receive PST.8-10 Even in patients with pathological complete response following PST whole breast irradiation is indicated after breast-conserving surgery.3,4 According to retrospective analyses the addition of radiation to PST and mastectomy reduces local regional recurrence and increases breast cancer specific survival for patients presenting with clinical T3 tumors or stage III and IV (ipsilateral supraclavicular nodal) disease and for patients with  four positive axillary nodes regardless of their response to PST.11 References 1. Nardone L, et al. Rays 22, 417, 1997 2. Colleoni M, et al. Eur J Cancer 34, 641, 1998 3. Pierce LJ, et al. Int J Radiot Oncol Biol Phys 23, 949, 1992 4. Ring A, et al. J Clin Oncol 21, 4540, 2003 5. Rouzier R, et al. J Clin Oncol 19, 3828, 2001 6. Webb A, et al. Proc Am Soc Clin Oncol 21, 46a, 2002 (abstr 183) 7. Pockaj AB, et al. Am Soc Clin Oncol, Educational Book, 40th Annual Meeting, June 5-8, 2004, New Orleans, LA, pp 8. Early Breast Cancer Trialists´ Collaborative Group. Lancet 355, 1757, 2000 9. Recht A, et al. J Clin Oncol 19, 1539, 2001 10. Buchholz TA. Am Soc Clin Oncol, Educational Book, 40th Annual Meeting, June 5-8, 2004, New Orleans, LA, pp 11. Huang EH, et al. J Clin Oncol 22, 4639, 2004

34 Endokrine Therapie des primären Mammakarzinoms

35 St. Gallen Therapieempfehlung
stark endokrin-ansprechend inkomplett nicht HER-2 negativ ET(ggf. zusätzlich CT gemäß Risiko) CT HER-2 positiv ET+ Trastuzumab+ CT Trastuzumab+ CT Goldhirsch et al, Ann Oncol 18: , 2007

36 EBCTCG Metaanalyse Tamoxifen vs nihil
HR 0,59 HR 0,66 3,6% 11,4% EBCTCG, Lancet 365: , 2005

37 Prämenopause Postmenopause

38 Metaanalyse Ovarielle Suppression
+4,3% +3,2% HR 0,83 HR 0,86 EBCTCG , Lancet 365: , 2005

39 HR 1,01 HR 0,99 ZEBRA – Überleben ER+
Jonat et al, J Clin Oncol 20: , 2002

40 ZEBRA – Amenorrhoe nach CMF
HR 0,65 Jonat et al, J Clin Oncol 20: , 2002

41 GnRH nach Chemotherapie
HR 0,88 HR 0,85 EBCOG, Lancet 369: , 2007

42 GnRH nach Chemotherapie – Einfluss des Alters
<=40 >40 EBCOG, Lancet 369: , 2007

43 (Chemo-)endocrine therapy
of premenopausal patients with endocrine responsive tumors High or intermediate risk Chemo  TAM 1a A ++ Chemo  TAM + GnRHa 1b B /- <40 yrs 2a C * Low or intermediate risk TAM alone 1a A ++ TAM + GnRHa 1b B + GnRHa alone 1b B +/- Oxford / AGO LoE / GR Best data is given by the meta-analysis from the early breast cancer trialists´ collaborative group for endocrine therapy with tamoxifen. There is more and more data available concerning GnRH-analogues. To have the optimal therapeutic effect, GnRH should be combined with tamoxifen. GnHR+/- Tamoxifen can be considered for certain subgroups (<40years, premenopausal E2 levels after chemotherpy). (Cave: most data have been shown in trials comparing GnRH with CMF). The combination of GnRH and aromatase inhibitors is not recomended at this point of time. Tamoxifen only can be considered in special cases if the patient does not consent or tolerate additional chemotherapy or GnRH therapy. * Study participation recommended

44 (Chemo-)endocrine therapy
of premenopausal patients with endocrine responsive tumors Oxford / AGO LoE / GR GnRH + AI 5 D +/-* AI alone 1c A - - AI after GnRHa (induced amenorrhea) 5 D - - Upfront AI in patients with chemotherapy-induced amenorrhea 4 C - - * Study participation recommended

45 Prämenopause Postmenopause

46 Sorgfältige individuelle Balance von Risiken und Nebenwirkungen
Die optimale adjuvante endokrine Therapie einer postmenopausalen rezeptorpositiven Patientin sollte einen Aromatasehemmstoff entweder initial oder sequentiell erhalten. Sorgfältige individuelle Balance von Risiken und Nebenwirkungen Winer et al, J Clin Oncol 23, 2005

47 Vorliegende Evidenz Howell, Lancet 366: , 2005

48 Offene Fragen Sollten Aromatasewirkstoffe Tamoxifen völlig ersetzen?
Welcher Aromatasewirkstoff ist der Beste? Welche Taktik ist die Beste? Lassen sich Subgruppen definieren? Wie lange müssen Aromatasewirkstoffe gegeben werden?

49 Was hilft uns bei dieser Frage weiter?
Nutzen für das Gesamtüberleben? Berechnungsmodelle? Tumorbiologie? Epidemiologie? Rezidivraten?

50 Tam / AI: Therapy duration and sequencing
Oxford / AGO LoE / GR Tam 5 (instead of 2 or 1) yrs 1a A ++ Anastrozole or Letrozole 5 yrs** 1b B ++ Being disease free after 2-3 yrs Tam: Exemestane or Anastrozole for pts.*** 1b B ++ Duration of AI up to 5 yrs 5 D +/-* Re-Initiation Tam (if therapy < 5 yrs)*** 2b B + So far, no conclusive data to favour either upfront or sequential AI ! The optimal duration of Tamoxifen treatment (20 mg / d) is considered to be 5 years, longer duration of tamoxifen therapy does not seem to be beneficial (Fisher 2001). However threre are two big studies investigating a longer duration of tamoxifen vs 5 years of tamoxifen which have closed accrural but have not been reported so far. A shorter therapy duration is less effective (EBCTCG 1998); If tamoxifen therapy was stopped early, re-newed therapy up to a total of 5 years may be beneficial (Gradishar 2002). At present, optimal sequencing of tamoxifen and aromatase inhibitors cannot be definitely decided. According to the recently published data, three scenarios for use of aromatase inhibitors are therefore possible: Up-front use, switch after 2-3 years, and extended adjuvant therapy after 5 years of tamoxifen therapy. In view of follow-up data published so far, total duration of adjuvant endocrine therapy in case of up-front or switch therapy, should not extend beyond a total of 5 years. As up-front therapy, anastrozole and letrozole are more effective than tamoxifen regarding DFS. An OS advantage has not been shown so far (ATAC Trialists´Group 2005, BIG 1-98 Collaborative Group 2005/2006). In a retrospective, hypothesis-generating study greatest DFS improvement with anastrozole was shown for patients with ER+PgR- tumors (Dowsett 2005) However in a recently published study this did not hold true (Dowsett 2006) collected blocks of the ATAC study were analyzed centrally for ER, PR and HER2. In this study the benefit of anastrozole over tamoxifen was similar for ER+ PR+ and ER+ PR- patients. The same results were obserevd in the BIG study where the benefit of letrozole in ER+ tumors was independent of the PR status. (Viale 2005). HER2 positivity was strongly associated with shorter TTR (anastrozole) or DFS (letrozole) for both tamoxifen and anastrozole or letrozole. Another 3 studies (IES, ITA, ABSCG 8) and a pooled analysis of 2 studies (ARNO 95+ABCSG 8) show a benefit for aromatase inhibitors in terms of DFS (Coombes 2004, Boccardo 2005, Jakesz 2005). In two single studies (IES update after 55 months and the ARNO study, Coombes 2007, Kaufmann 2006) also an overall survival benefit has been observed for those pts beeing relapse free after 2-3 years tamoxifen and switching to an AI. It is important to stress that the randomization in these trials was in contrast to the BIG, ATAC and ABCSG8 studies not done upfront but after 2-3 years of tamoxifen treatment. Only pts without relapse were eligible for ARNO, IES and ITA, and therfore patients with relapse in the first 2-3 years were excluded in these studies. Since the patient collectives are distinctively different to the trials with upfront randomization comparisons between the individual trials can not be made. For this reason we have no conclusive data to favour either upfront or sequential AI therapy. We have to wait for the final results of the BIG-1-98 study. The ITA, ARNO 95 and ABSCG 8 trials tested anastrozole, whereas exemestane was used in the IES trial. In the ARNO 95 and ABCSG 8 trials patients did only receive adjuvant endocrine therapy and no adjuvant chemotherapy. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001;93: Gradishar WJ, Hellmund R. A rationale for the reinitiation of adjuvant tamoxifen therapy in women receiving fewer than 5 years of therapy. Clin Breast Cancer 2002;2:282-6. Viale G, Regan M, Dell'Orto P, et al. Central review of ER, PgR and HER-2 in BIG 1-98 evaluating letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Breast Cancer Res Treat 2005;94(Suppl 1): Abstr. 44. Dowsett M et al. relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial. Breast Cancer Res Treat 2006;100 (suppl1):abstract 48 *study participation recommended **so far no OS advantage shown ***up to a total of 5 yrs of endocrine therapy

51 Endocrine therapy after 5 years of tamoxifen
Oxford / AGO LoE / GR Letrozole 5 yrs 1b A + node-positive disease 1b B ++ long tamoxifen-free interval (up to 30 months) 4 D + Anastrozole 3 yrs 2b B + Exemestane 5 yrs 2ba B + Tam > 5 yrs 2ba C + As extended adjuvant therapy after 5 years of tamoxifen therapy letrozole (vs. placebo) and anastrozole (vs. nil) are superior to no additional endocrine therapy with regard to DFS (Goss 2005, Jakesz 2005). In node-positive patients, extended adjuvant therapy with letrozole therapy resulted in a significant OS advantage (Goss 2005). Letrozole could be started up to 30 months after cessation of tamoxifen (Goss 2005). An intent to treat analysis of the NSABP-B33 study showed a trend towards better DFS and a significant better RFS in favour of extended adjuvant therapy with exemestane compared to placebo (Due to the results of the MA.17 study recruitment in the B33 study was stopped and unblinded October At this time f 3000 planned patients were enrolled. Goss PE, Ingle JN, Palmer MJ, et al. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs. placebo) post unblinding. Breast Cancer Res Treat 2005;94(Suppl 1):S11, Abs 16. Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97: Jakesz R, Samonigg H, Greil R, et al. Extended adjuvant treatment with anastrozole: results from the Austrian Breast an Colorectal Cancer Study Group Trial 6a (ABSCG 6a). J Clin Oncol 2005;23(Suppl.):10S, Abs 527 Mamounas E et al.Benefit from exemestane as extended adjuvant therapy after 5 years of tamoxifen intent to treat analysis of the NSABP-B33. Breast Cancer Res and Treat 2006; abst 49. Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23: Wasan KM, Goss PE, Pritchard PH, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 2005;16:

52 CYP2D6 und Tamoxifenmetabolismus
Goetz et al, J Clin Oncol 23: , 2005

53 „Zielgerichtete“ Therapie
                              PD Dr. med. Achim Rody 53

54 „The hallmarks of cancer“

55 ER + 65-75 % alle Mamma- karzinome HER-2 + 15-20 % basaloid

56 „zielgerichtete Therapie“
„old dogs“ Doxorubicin/ Epirubicin Topoisomerase IIα Paclitaxel/ Docetaxel Mapτ Vinorelbin Mikrotubuli Capecitabine Dihydropyrimidin-dehydrogenase Tamoxifen ER-α „new biologicals“ Trastuzumab Her-2 Lapatinib Her-1, Her-2 Bevacizumab VEGF Everolimus mTOR Sunitinib PGFR, VEGFR, KIT, FLT3

57 Angriffspunkte „Mab´s“ „Nib´s“ 1. Signal Blockade Zelläußeres
(z.B. Hormone, Eiweißmoleküle) Blockade (Antikörper, Produktionshemmung) Zelläußeres „Mab´s“ Signalempfänger (Rezeptoren) Blockade (Antikörper) 2. Signal (z.B. „Kinasen“, Eiweißmoleküle) Hemmung („small molecules“, Kinasehemmer) „Nib´s“ Zellinneres Zellwachstum (z.B. DNA-Verdopplung) Hemmung (Chemotherapie)

58 Überlebensvorteil durch Trastuzumab
OS benefit Median follow-up, years HERA CTxH 1 year 2 B-31 / N9831 ACPH 3 BCIRG 006 ACDH 3 BCIRG 006 DCarboH 3 References Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512. Slamon D et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, December 2006. Smith IE et al. Lancet 2007; 369: Favours trastuzumab 1 Favours no trastuzumab 2 HR Slamon D et al 2006; Perez EA et al 2007; Smith IE et al 2007

59 Problemfall pT1a N0 M0 G2 ER+ PR+ Her-2 3+ Trastuzumab ? Guidelines:
NCCN: Trastuzumab > 1cm AGO: nodal-negatives MaCa mit zusätzlichen Risikofaktoren (z.B. > 1cm)

60 GeparQuattro: pCR HER2-positive Patienten
EC Doc DocX Doc-X pCR(%) Trastuzumab EC Doc DocX Doc-X 45.5% 20.6% Reference Untch M et al. EJC Suppl 2008; 6: 47, abs 1LB. Untch M et al 2008

61 Neoadjuvant Herceptin (NOAH)
HER2-positive LABC (IHC 3+ or FISH+) HER2-negative LABC (IHC 0/1+) n=115 n=113 n=99 H + AT q3w x 3 AT q3w x 3 AT q3w x 3 H + T q3w x 4 T q3w x 4 T q3w x 4 H q3w x 4 + CMF Tag 1, 8 q4w x 3 CMF Tag 1, 8 q4w x 3 CMF Tag 1, 8 q4w x 3 OP OP OP H continued q3w x 7 Radiotherapiea Radiotherapiea Radiotherapiea LABC: lokal fortgeschrittener Brustkrebs H, Herceptin (8 mg/kg Initialdosis danach 6 mg/kg); A, Doxorubicin (60 mg/m2); T, Paclitaxel (150 mg/m2); CMF, Cyclophosphamid (600 mg/m2)/Methotrexat (40 mg/m2)/5-Fluorouracil (600 mg/m2) aHormonrezeptor-positive Patienten erhielten adjuvant Tamoxifen Gianni et al., ASCO 2007; #532 61

62 Ansprechen: pCR Gianni et al., SABCS 2008, #31

63 Überleben medianes f/u 3 Jahre
EFS OAS Gianni et al., SABCS 2008, #31

64 Trastuzumab und Pertuzumab binden an verschiedene Epitope der extrazellulären Domäne des HER2-Rezeptors Trastuzumab Pertuzumab Verhinderung der Rezeptor- Dimerisierung potenter Inhibitor der HER-vermittelten Signaltransduktion Aktivierung der ADCC Steigerung der HER2-Internalisierung Inhibition des “sheddings” und dadurch keine Bildung von p95 Aktivierung der ADCC Hubbard 2005 64

65

66 Kumulative Inzidenz 5-Jahres follow-up
Tan-Chiu et al., JCO, 23: , 2005 Rastogi et al., ASCO 2007, #513 66

67 Kardiale Risikofaktoren Alter > 50 J. Antihypertensive Medikation
Baseline LVEF < 55 % LVEF nach Anthrazyklinen < 55 % Prophylaxe mit ACE-Hemmern ? Rastogi et al., ASCO 2007, #513

68

69 PFS und OAS PFS OAS ZNS-Metastasen 4 (L+C) vs. 11 (C)
Geyer CE et al., NEJM, 355: , 2006 69

70 Lapatinib 1000 mg qd + continuation of Herceptin 2 mg/kg qw (n=148)
EGF104900: study design MBC HER2-positive (FISH) Progression under Herceptin-based therapy (prior chemo / Herceptin therapies = 4-5 / 3) R Lapatinib 1000 mg qd + continuation of Herceptin 2 mg/kg qw (n=148) Lapatinib 1500 mg qd (n=148) Crossover PD after 4 wks (73 pts) O’Shaughnessy et al., ASCO 2008, #1015

71 Progression-free survival (PFS)
1.0 0.8 Herceptin plus lapatinib Lapatinib HR = 0.73; p = 0.08 0.6 Probability 0.4 0.2 0.0 10 20 30 40 50 60 Weeks Pts at risk L LH 53 73 21 42 13 27 5 8 2 O’Shaughnessy et al., ASCO 2008, #1015

72 Lapatinib Monotherapy
EGF105084: Study Design Stratification: PS and number of prior trastuzumab-containing regimens Lapatinib Monotherapy 750 mg BID PD Extension arms 88 % > 3 Chemotherapien (adjuv./ pall.) Trastuzumabvorbehandlung γ-Knife bzw. Ganzhirnradiatio Lin et al., ASCO 2007, #1012 72

73 Volumetric Reduction in CNS Lesions (Lapatinib Monotherapy)
Median (range), cm3 ≥ 50% CNS volumetric tumor reduction Absolute tumor volumetric reduction 19/241 (7) 3.1 ( ) ≥ 20%* CNS volumetric tumor reduction Absolute tumor volumetric reduction 46/241 (19) 1.9 ( ) *Exploratory analysis Lin et al., ASCO 2007, #1012 73

74

75 Studien-Design 1 Beendigung ALLER (neo)-adjuvanten Chemotherapien vor Beginn der gezielten Krebstherapie Lokal bestimmter HER2-positiver, invasiver Brustkrebs Zentral bestimmter HER2+; ER und PgR Operation, Beendigung der (neo-)adjuvanten, Anthracyclin-basierten Chemotherapie (aus zugelassener Liste ausgewählt) LVEF  50% 52 WOCHE N Trastuzumab Alle 3 Wochen Lapatinib Trastuzumab Wöchentlich (12 Wochen) Lapatinib + Trastuzumab Alle 3 Wochen Auswaschphase (6 Wochen) Lapatinib (34 Wochen) Patientinnen mit ER- oder PgR-positiven Tumoren erhalten eine endokrine Therapie, die dem menopausalen Zustand entsprechend ausgewählt wird; die endokrine Therapie wird nach Ende der Chemotherapie eingeleitet und gleichzeitig mit der gezielten Krebstherapie verabreicht (geplant sind mindestens 5 Jahre) Strahlentherapie falls notwendig 75

76 Studien-Design 2 Paclitaxel als gleichzeitig mit der gezielten Therapie nach jeder A-basierten, (neo)-adjuvanten Chemotherapie Lokal bestimmter HER2-positiver, invasiver Brustkrebs Zentral bestimmter HER2+; ER und PgR Operation, Beendigung der (neo-)adjuvanten, Anthracyclin-basierten Chemotherapie (aus zugelassener Liste ausgewählt) LVEF  50% 52 WOCHE N Paclitaxel wöchent-lich 12 Wochen Trastuzumab wöchent- lich 12 Wochen  Paclitaxel wöchent- lich 12 Wochen Lapatinib 52 Wochen Paclitaxel wöchent- lich 12 Wochen Trastuzumab wöchent- lich 12 Wochen  Paclitaxel wöchent- lich 12 Wochen Lapatinib + Trastuzumab wöchent- lich 12 Wochen  Lapatinib + Trastuzumab alle 3 Wochen 40 Wochen Trastuzumab Alle 3 Wochen 40 Wochen Auswasch-phase 6 Wochen Lapatinib 34 Wochen 76

77 52 weeks of anti-ErbB2 therapy
NEO-ALTTO FEC  3 lapatinib lapatinib Invasive breast cancer HER2+ T>2 cm (inflammatory BC excluded) LVEF  50% N=450 R A N D O M I Z E paclitaxel Surgery trastuzumab trastuzumab paclitaxel Stratification: T< 5 cm versus T> 5 cm ER or PgR + versus both ER and PgR – N0-1 versus N ≥2 Conservative surgery or not lapatinib lapatinib trastuzumab trastuzumab paclitaxel weeks 9 weeks 34 weeks 52 weeks of anti-ErbB2 therapy 77

78 Hemmung der Tumorangiogenese
78

79 Bevacizumab: Effektivität
Miller KD et al., NEJM, 357: , 2007

80 AVADO: doppelblind, plazebokontrolliert
1st-line lokal rezidiviertes oder metast. Mamma-karzinom (n=705) Stratifizierung nach: Region vorausgegangener Taxantherapie/ Zeit bis zum Rezidiv seit adj.Chemotherapie Messbare Erkrankung Hormonrezeptor-Status Behandlung mit Plazebo/ Bevacizumab bis zum Progress Alle Patientinnen erhielten die Option auf eine Second-Line- Therapie mit Bevacizumab Docetaxel* 100mg/m2 + Plazebo q3w Docetaxel* + Bevacizumab 7.5mg/kg q3w Docetaxel* + Bevacizumab 15mg/kg q3w Primärer Endpunkt: progressionsfreies Überleben Sekundäre Endpunkte: Gesamtansprechrate und Ansprechdauer, Zeit bis zum Therapieversagen, Gesamtüberleben, Sicherheit, Lebensqualität AVADO was a randomized, double-blind, placebo-controlled phase III study. Patients with locally recurrent or metastatic breast cancer were randomized to one of three treatment arms; patients were stratified by: region, presence or absence of measurable disease, hormone receptor status, disease-free interval and prior taxane therapy. Patients were randomized to receive docetaxel 100mg/m2 every 3 weeks, for a maximum of nine cycles, with either placebo or bevacizumab. Dose reduction of docetaxel to 75mg/m2 and/or 60mg/m2 was permitted in the event of toxicity. Bevacizumab was given at either 7.5 or 15mg/kg every 3 weeks. Patients continued to receive placebo or bevacizumab until disease progression. All patients were given the option to receive bevacizumab in combination with their second-line chemotherapy regimen. The primary endpoint of the trial was progression-free survival. Secondary endpoints were overall response rate, duration of response, time to treatment failure, overall survival, safety and quality of life. AVADO was a randomised, double-blind, placebo-controlled phase III study Patients with locally recurrent or metastatic breast cancer were randomised to one of three treatment arms; patients were stratified by: region, presence or absence of measurable disease, hormone receptor status, disease-free interval and prior taxane therapy. Patients were randomised to receive docetaxel 100mg/m2 every 3 weeks, for a maximum of nine cycles, with either placebo or Avastin. Dose reduction of docetaxel to 75mg/m2 and/or 60mg/m2 was permitted in the event of toxicity. Avastin was given at either 7.5 or 15mg/kg every 3 weeks. Patients continued to receive placebo or Avastin until disease progression. All patients were given the option to receive Avastin in combination with their second-line chemotherapy regimen (=cross-over Setting). The primary endpoint of the trial was progression-free survival. Secondary endpoints were overall response rate, duration of response, time to treatment failure, overall survival, safety and quality of life. *Docetaxel würde maximal für neun Zyklen gegeben; ein früheres Absetzen war erlaubt. Miles et al., ASCO 2008, LBA#1011

81 AVADO: PFS (ITT); medianes f/u 10,2 Mo
Plazebo + Docetaxel (n=241) Bev 7.5† + Docetaxel (n=248) Plazebo + Docetaxel (n=241) Bev 15† + Docetaxel (n=247) HR + 95% CI (nicht strat.) 0.79 (0.63–0.98) p=0.0318 HR + 95% CI (nicht strat.) 0.72 (0.57–0.90) p=0.0099 HR + 95% CI (stratifiziert*) 0.69 (0.54–0.89) p=0.0035 HR + 95% CI (stratifiziert*) 0.61 (0.48–0.78) p<0.0001 Median 8,0 8,7 Median 8,0 8,8 For patients randomised to Avastin 7.5mg/kg, the unstratified hazard ratio for progression-free survival was 0.79, p= Median progression-free survival was 8.0 months in the placebo arm and 8.7 months in this Avastin arm. The unstratified hazard ratio for progression-free survival in the Avastin 15mg/kg trial arm versus placebo was 0.72, p= Median progression-free survival was 8.8 months in this Avastin arm. Here, median PFS is not entirely reflective of treatment effect as it is based on only one point on the curve, whereas hazard ratio is representative of the whole study period. In the analysis for FDA purposes, which is the stratified analysis with data censored for non-protocol therapy before disease progression (patients with NPT before PD: 3% in placebo arm, 4% in 7.5mg/kg Avastin arm and 3% in 15mg/kg Avastin arm), the hazard ratios for PFS were 0.69 for the lower and 0.61 for the higher Avastin dose. Miles et al., ASCO 2008, LBA#1011

82 TBP (GBG26/BIG3-05): Study Design
X: Capecitabine 2500 mg/m² d 1 – 14 q 22 R XH: Capecitabine 2500 mg/m² d 1 – 14 q 22 and continuation of Trastuzumab 6 mg/kg q22 n=78 n=78 Von Minckwitz et al., ASCO 2008, #1025 82

83 Time To Progression median follow-up: 15.6 mos X : 5.6 (4.2 - 6.3) mos
XH : 8.2 ( ) mos HR=0.69 (two-sided p=0.034; one-sided p=0.015) P<0.0467 median follow-up: 15.6 mos Von Minckwitz et al., ASCO 2008, #1025 83

84 Overall Survival X : 20.4 (17.8 – 24.7) mos
XH : 25.5 (19.0 – 30.7) mos HR=0.76 (two-sided p=0.26; one-sided p=0.13) Von Minckwitz et al., ASCO 2008, #1025 84

85

86 „new biologicals – new side effects“
Pathophysiologie unklar Anti-EGFR-mAb, EGFR-TKI Lapatinib+Capecitabine (any: 60 %; IV°: 1%) Herzinsuffizienz Trastuzumab: 3,8 % Lapatinib: 1,6 % Akne % EGFR-Inhibition (outcome-assoziiert) dosisabhängig, Antiseptika, Erythromycin Antiangiogenese: art. Hypertonie Wundheilungsstörung Blutung Antiangiogenese: Proteinurie Therapieabbruch > 3g/24 h Hand-Fuß-Syndrom

87 Zukunft Multi-TKI Sunitinib (VEGFR-1/2/3; PDGFR-α/β; c-Kit)
Pazopanib (VEGFR-1/2/3; PDGFR-α/β; c-Kit) Sorafenib (VEGFR-1/2/3; PDGFR-α/β; c-Kit; Flt-3; Raf) Neratinib (HKI-272; ErbB-1/2/4) Kombinationen TKI + AK TKI + Chemo TKI + enokrine Therapie TKI + TKI … „downstream“ Inhibition mTOR-Inhibition (RAD001) Blockade alternativer Pfade z.B. Her-2 + Angiogenese (Trastuzumab+Bevacizumab)

88 was brauchen wir ? was haben wir ?
neue Substanzen; neue Kombinationsmöglichkeiten wenig Wissen über Wirksamkeit (wie, wann, bei wem ?) was brauchen wir ? neue Klassifikation unter Einsatz von Biomarkern (a-priori) neue Endpunkte innovative Biostatistik neue Studiendesigns neue Hypothesen neue translationale Fragestellungen (a-priori, nicht a-posteriori)