Adjuvante Therapie des. Mammakarzinoms

Transkript

1 Onkologie in Klinik und Praxis Wilhelminenspital, Adjuvante Therapie des Mammakarzinoms Günther Steger Universitätsklinik tsklinik für r Innere Medizin I Klinische Abteilung für Onkologie Medizinische Universität Wien

2 Risks and Benefits of adjuvant Treatment Optimization of therapies No benefit Death despite therapy % of surviving patients Characterization of predicitive factors Adjuvant Therapy Control Benefit No benefit Survival without therapie Jahre

3 Risks and Benefits of adjuvant Treatment No benefit Death despite therapy % of surviving patients Adjuvant Therapy Control Benefit No benefit Survival without therapie Jahre

4 CONSENSUS St. Gallen 2005 THEMEN und FRAGEN Was ist Lymphknoten positiv (N+) Timing und Dauer der Chemotherapie Timing der Chemo-Hormontherapie Rolle der Aromataseinhibitoren Rolle der Taxane Rolle des Dose-Density-Konzeptes

5 CONSENSUS St. Gallen 2005 Rolle der Aromataseinhibitoren?

6 ATAC - Trial (Arimidex or Tamoxifen Alone and in Combination) Anastrozol 1mg/d + Tamoxifen Placebo Anastrozol Placebo + Tamoxifen 20mg/d Anastrozol 1mg/d + Tamoxifen 20mg/d

7 Patientinnen (%) ATAC: Mammakarzinom-Ereignisse* KM Kurven für HR+ Patientinnen HR+ ITT A T Anastrozol (A) Tamoxifen (T) HR 0,74 0,79 95% CI (0,64 0,87) (0,70-0,90) p-wert 0,0002 0,0005 Absoluter Unterschied 0 1,7% 1,7% 2,4% 2,8% 3,7% Follow-up Dauer (Jahre) A T *TTR = Time to Recurrence, Todesfälle vor Krankheitsreignis nicht miteingeschlossen Howell, SA 2004

8 BIG Studie Letrozol vs. Tamoxifen Letrozol A und C Tamoxifen B und D Ereignisse nach Switch in Arm C und D wurden nicht berücksichtigt. N=8.010, Follow-up 25,6 Monate Letrozol Tamoxifen 2 Armoption 4 Armoption

9 BIG1-98 DFS (25,8 Mon F/U) Abs. Diff. 1,5%

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12 THE NEW ENGLAND JOURNAL OF MEDICINE

13 STUDIENDESIGN

14 STUDIENERGEBNISSE: WIRKSAMKEIT PRIMÄRER ENDPUNKT: krankheitsfreies ÜBERLEBEN 100 Exemestane Women surviving event-free (%) 75 Tamoxifen Hazard ratio=0.68 (95% CI: ) Log-rank test: p= No. events/at risk Exemestane Tamoxifen Years from randomisation 0 / / / / / / / / / / 185 events occurring more than 4 years after randomisation Coombes et al, N Engl J Med 350: , 2004

15 ABCSG 8 - ARNO 95 Alle Patientinnen (n=3.224): postmenopausal OP +/- RT Keine Chemo hormonrezeptorpositiv N0 und N+ Tamoxifen 2 Jahre R Tamoxifen 3 Jahre Anastrozol 3 Jahre Gesamt 5 Jahre Jakesz, SA 2004

16 ABCSG 8-ARNO Effektivität EFS und Metastasierung EFS* 100 (%) 95 AN A DDFS (%) ANA % ANA vs TAM p= HR 0.60 [95% CI ] 0 At risk: Ereignisfreie Zeit (Jahre)* 5 TAM ANA *Startpunkt = 2 Jahre nach OP TA M TAM 84 HR 0.61 [95% CI ] 0-39% p= DRFS Zeit (Jahre) Jakesz, SA 2004

17 CONSENSUS St. Gallen 2005 Aromataseinhibitoren Receptorstatus HR pos HR uncertain HR neg Meno-status Prä Post Prä Post Prä Post N0 low Tam Tam or Tam Tam or or AI or nil or AI or 0 Chemotherapy nil nil (Tam > AI) (Tam >AI) (6xTriplet) N0 + risk Tam +/- Tam or AI CT>Tam CT>Tam N+ average OFS CT>Tam (+/-OFS) or (= N1-3) or or or CT>AI Chemotherapy CT>Tam CT>AI CT alone or (6 months?) +/-OFS or CT> +/- Taxan or CT> Tam>AI OFS T>AI high risk CT>Tam CT>T or N4+ +/-OFS CT>AI CT (6xTriplet) Chemotherapy Ari or Exe + Taxan (6 months?) Ari>2/3a T > ET + Taxan Let >5aT

18 CONSENSUS St. Gallen 2005 Rolle der Taxane?

19 CALGB 9344 / Intergroup 0148 n = 3121 DFS RR: Recur: 17% AC+Paclitaxel AC C: 600 mg/m2 P 175 mg/m2 (3 h) 6.2% p=0.008 None A: 60 = 75 = 90 mg/m2 Henderson et al. JCO 2003 Recommended Tam if ER (+) After chemorx OS AC AC+Paclitaxel 5.8% p=0.01 RR: Death 18%

20 NSABP B-28: ASCO 2003 w/ med. f/u 64 Months 1.0 Fig. 1: B-28 DFS Rx Events RR 0.9 Proportion Disease-Free AC N=1528, 461 Events AC->T N=1531, 400 Events RR=0.83, p=.008 +P P 461 ( ) Time to Event (months) 1.0 Fig. 2: B-28 Survival RR 17% p=0.008 Rx Deaths RR Proportion Alive AC N=1529, 255 Deaths AC->T N=1531, 243 Deaths RR=0.94, p=.46 +P P 255 ( ) RR 6% p= Time to Death (months)

21 BCIRG001-Design F A C 5-FU 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 R Every 3 weeks x 6 cycles Stratification Nodes Center T A C Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2

22 1.0 BCIRG months data Disease free - Survival (ITT) Cumulative probability TAC FAC N Events HR P-value Stratified Log Rank TAC % 68% 7% 0.0 FAC DFS Time(months)

23 1.0 BCIRG months data Overall Survival (ITT) TAC 87% Cumulative Probability FAC N Events HR P-value Stratified Log-Rank TAC % 6% 0.0 FAC Survival Time (months)

24 6Cycles of FEC 100 vs 3 FEC 100 Followed by 3 Cycles of Docetaxel for Node-Positive Breast Cancer Patients: Analysis at 5 Years of the Adjuvant PACS 01 Trial Henri Roché, Pierre Fumoleau, Marc Spielmann, Jean-Luc Canon, Thierry Delozier, Pierre Kerbrat, Daniel Serin, Alain Lortholary, Catherine de Ghislain, Patrice Viens, Jean-Pierre Bergerat, Jean Genève, Anne-Laure Martin, Bernard Asselain for the PACS Study Group PACS 01

25 Treatment Protocol PACS 01 S U R G E R Y Stratified on: Center Age: < or 50 N: 1-3; 4 R 6FEC100: ARM A Fluorouracil 500 mg/m² d1 Epirubicin 100 mg/m² d1 Cyclophosphamide 500 mg/m² d1 6 cycles every 21 days 3FEC100-3 Docetaxel: ARM B 3 cycles of FEC 100 every 21 days followed by 3 cycles of Docetaxel 100 mg/m² d1 every 21 days Radiotherapy delivered within 4 weeks after the last chemotherapy cycle Tamoxifen 20 mg/day for 5 years prescribed in hormone-receptor positive post-menopausal women after chemotherapy

26 Hematologic Toxicity PACS 01 Per Patient 6FEC100 3FEC100-3D χ² test Neutropenia gr 3-4 (d21) Cycle 1 to 3, % Cycle 4 to 6, % < Febrile neutropenia,cy.4 % Infection gr 3-4, % Anemia gr 3-4, % Thrombocytopenia gr 3-4, % G-CSF/cycle, per cycle < Cycle 1 to 3, % Cycle 4 to 6, % < 0.001

27 Cardiac Toxicity PACS 01 Patients, n (%) Events, n CHF LVEF Arrhythmia 2 Others 2 Cardiac death* 6FEC (1.3) FEC100-3D 4 (0.4) χ² test myocardial infarct, dyspnea / pericarditis, menace syndrome * cardiogenic shock / sudden death

28 DFS at 5 years, ITT PACS FEC100-3Docetaxel: 78.3% Probability Relapses = (21.7%) 264 (26.5%) Log-rank unadjusted P-value = Log-rank adjusted P-value = FEC100: 73.2% HR (Cox model) = 0.83 [ ], P-value = Time (years)

29 OS by Treatment Arm, ITT PACS Death = (10.0%) 135 (13.5%) 3FEC100-3Docetaxel: 5-year OS = 90.7% Probability FEC100: 5-year OS = 86.7% Log-rank unadjusted P-value = Log-rank adjusted P-value = HR (Cox model) = 0.77 [ ], P-value = Time (years)

30 CONSENSUS St. Gallen Rolle der Taxane Receptorstatus HR pos HR uncertain HR neg Meno-status Prä Post Prä Post Prä Post N0 low Tam Tam or Tam Tam or or AI or nil or AI or 0 Chemotherapy nil nil (Tam > AI) (Tam >AI) (6xTriplet) N0 + risk Tam +/- Tam or AI CT>Tam CT>Tam N+ average OFS CT>Tam (+/-OFS) or (= N1-3) or or or CT>AI Chemotherapy CT>Tam CT>AI CT alone or (6 months?) +/-OFS or CT> +/- Taxan or CT> Tam>AI OFS T>AI high risk CT>Tam CT>T or N4+ +/-OFS CT>AI CT (6xTriplet) Chemotherapy Ari or Exe + Taxan (6 months?) Ari>2/3a T > ET + Taxan Let >5aT

31 CONSENSUS St. Gallen Rolle der Taxane Receptorstatus HR pos HR uncertain HR neg Meno-status Prä Post Prä Post Prä Post N0 low Tam Tam or Tam Tam or or AI or nil or AI or 0 Chemotherapy nil nil (Tam > AI) (Tam >AI) (6xTriplet) N0 + risk Tam +/- Tam or AI CT>Tam CT>Tam N+ average OFS CT>Tam (+/-OFS) or (= N1-3) or or or CT>AI Chemotherapy CT>Tam CT>AI CT alone or (6 months ) +/-OFS or CT> +/- Taxan or CT> Tam>AI OFS T>AI high risk CT>Tam CT>T or N4+ +/-OFS CT>AI CT (6xTriplet) Chemotherapy Ari or Exe + Taxan (6 months ) Ari>2/3a T > ET + Taxan Let >5aT

32 ADJUVANTE THERAPIE DES MAMMAKARZINOMS ASCO 2005 OXFORD STYLE DEBATES IST HERCEPTIN R EIN NEUER STANDARD FÜR HER2-positiven MAMMAKARZINOME? G.Steger Medizinische Universität Wien

33 HERCEPTIN - Adjuvante Studien Zusammenfassung der 4 Haupt-Studien NSABP B31 Intergroup N9831 AC x 4 AC x 4 AC x 4 AC x 4 AC x 4 P q3w x 4 P q3w x 4 + H P qw x 12 P qw x 12 H P qw x 12 + H gepoolte Interim-Analyse ASCO 5/2005 n=3351 AC x 4 Docetaxel q3w x 4 BCIRG 006 AC x 4 Docetaxel q3w x 4 + H H q3w* Cis/carboplatin + Docetaxel q3w x 6 + H H q3w* HERA Trial *q3w with 6mg/kg H = Herceptin Jede CT ± RT ± Tam H q3w* x 12 Months H q3w* x 24 Months Kontrolle Interim-Analyse ASCO 5/2005 n=3090

34 Disease-Free Survival % AC T AC TH N Events AC T AC TH % 75 % 85 % 67 % HR=0.48, 2P=3x10-12 Years From Randomization B31/N983 1

35 Forest Plot For Disease-Free Survival ALL DATA Age Hormone Receptor Positive Negative Tumor Size No. Positive Nodes Protocol 4.1cm cm <2.0 cm N9831 NSABP B Hazard Ratio

36 Disease-Free Survival 100 B-31 N9831 AC TH 100 AC TH 90 87% 85% 90 87% 86% % AC T 74% 66% AC T 78% 68% 60 N Events N Events 60 AC T AC T AC TH AC TH HR=0.45, 2P=1x10-9 HR=0.55, 2P= Years From Randomization

37 Time to First Distant Recurrence AC TH AC->T+H AC T AC->T 90% 90% 90% % N Events N Events AC TH AC->T AC T AC->T+H HR=0.47, 2P=8x % 74% 74% HR=0.47, 2P=8x Years From Randomization B31/N9831

38 B-31/N9831 Survival AC T 94% 92 % AC TH 91 % 87 % N Deaths AC T AC TH HR=0.67, 2P=0.015 Years From Randomization B31/N983 1

39 % B-31: Cumulative Incidence of Cardiac Events in the Evaluable Cohort 6 4 Arm 2: AC T +H N=830, 30 CHFs, No Cardiac Deaths HR= % Yrs Post Day 1 Cyc Cum Inc Arm 1 (%) 0.3 Cum Inc Arm2 (%) 2.5 No. At Risk Arm 1: AC T N=794, 3 CHFs, 1 Cardiac Death 0.7% Years Post Day 1 Cyc 5 Cohort Arm 1 Evaluable Cohort Arm 2 Evaluable Cohort

40 HERA TRIAL DESIGN Women with HER-2 2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT) ± radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine e therapy, age, region Randomization Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 1 year Observation

41 DISEASE-FREE SURVIVAL % alive 100 and 90 disease free year trastuzumab Observation Events 2-yr DFS % HR [95% CI] p value [0.43, 0.67] < Months from randomization No. at risk

42 DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation All Nodal status Any, neo-adjuvant chemotherapy 0 pos, no neo-adjuvant chemotherapy 1-3 pos, no neo-adjuvant chemotherapy 4 pos, no neo-adjuvant chemotherapy Adjuvant chemotherapy regimen No anthracycline or taxane Anthracycline, no taxane Anthracycline + taxane Receptor status/endocrine therapy Negative Pos + no endocrine therapy Pos + endocrine therapy Age group <35 yrs yrs yrs 60 yrs Region Europe, Nordic, Canada, SA, Aus, NZ Asia Pacific, Japan Eastern Europe Central + South America Hazard n ratio Favors 1 Favors 2 trastuzumab observation

43 SAFETY ANALYSIS POPULATION Cardiotoxicity Decrease by 10 EF points and LVEF < 50% Same LVEF criteria and symptomatic CHF NYHA class III/IV, confirmed by cardiologist Observation N= % 0 % (95% CI: ) 0.21) 1 year trastuzumab N= % 0.5% (95% CI: ) Cardiac death 0.1% 0%

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45 ADJUVANTE THERAPIE DES MAMMAKARZINOMS ASCO 2005 OXFORD STYLE DEBATES IST HERCEPTIN R EIN NEUER STANDARD FÜR HER2-positiven MAMMAKARZINOME? JA! G.Steger Medizinische Universität Wien

46 BCIRG 006 SABCS 2005 AC T 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 Her2+ (Central FISH) N+ or high risk N- N=3,222 Stratified by Nodes and Hormonal Receptor Status AC TH TCH 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 1 Year Trastuzumab 6 x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 1 Year Trastuzumab Slamon D., SABCS 2005

47 % Disease Free Patients Disease Free Survival Events 93% 91% 86% AC->T AC->TH TCH 86% 80% 77% 84% 80% 73% HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P< HR (TCH vs AC->T) = 0.61 [0.47;0.79] P= Year from randomization

48 Disease Free Survival AC-T n=1,073 AC-TH n=1,074 TCH n=1,075 Patients with event Observed p-values p = TCH AC-TH p = p = 0.16

49 Clinically significant cardiac events as per independent review panel AC-T AC-TH TCH n=1,050 n=1,068 n=1,056 Patients % 0.95% 2.34% 1.33% (95% C.I.) (0.46% %) (1.52% %) (0.73% %) P = P = 0.11 P = 0.54

50 HERCEPTIN - Adjuvant Studies Summary of the 4 Main Studies NSABP B31 AC x 4 AC x 4 Paclitaxel q3w x 4 Paclitaxel q3w x 4 + H Intergroup N9831 AC x 4 AC x 4 AC x 4 Paclitaxel qw x 12 Paclitaxel qw x 12 Paclitaxel qw x 12 + H H AC x 4 Docetaxel q3w x 4 BCIRG 006 AC x 4 Docetaxel q3w x 4 + H H q3w* Cis/carboplatin + docetaxel q3w x 6 + H H q3w* HERA Trial *q3w with 6mg/kg H = Herceptin any CT ± RT ± Tam H q3w* x 12 months H q3w* x 24 months Control

51 HERCEPTIN - Adjuvant Studies Summary of the 4 Main Studies NSABP B31 AC x 4 AC x 4 P q3w x 4 P q3w x 4 + H ASCO 5/2005 Relapses: -52% Intergroup N9831 BCIRG 006 AC x 4 AC x 4 AC x 4 AC x 4 AC x 4 P qw x 12 P qw x 12 H P qw x 12 + H D x 4 D x 4 + H Cis/carboplatin + Dx 6 + H H q3w* H q3w* Deaths: -32% SABCS 12/2005 Relapses: -52% -39% HERA Trial *q3w with 6mg/kg H = Herceptin any CT ± RT ± Tam H q3w* x 12 Months H q3w* x 24 Months Kontrolle ASCO 2005/06 Relapses: -50% Deaths: -24%

52 Brustkrebssterblichkeit in Österreich 1.2 Standardisierte Sterblichkeitsrate

53 ADJUVANTE THERAPIE Wie kann Fortschritt erzielt werden? TEILNAHME AN KLINISCHEN STUDIEN ABCSG - Studie 12 (präm, Rez +) ABCSG - Studie 15 (postm, Rez +, DCIS) ABCSG - Studie 16 (postm, Rez +/Planung) ABCSG -Studie 18 (postm, Rez +, AI-Th.) ABCSG - Studie 19 / HERA (HER2 +++) ABCSG - Studie 21 (Rez +, DTC pos) ABCSG Studie 23 (postm., Rez +) ABCSG Studie 24 (präop)..... CONCENSUS - MEETING St. Gallen 2007

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