Adjuvant Chemotherapy + Trastuzumab

Transcription

1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Adjuvant Chemotherapy + Trastuzumab (Optimal Drugs / Dosage / Trastuzumab)

2 Adjuvant Chemotherapy (Optimal Drugs / Optimal Dosage / Trastuzumab) Version 2002: Möbus / Nitz Version : Harbeck / Jackisch / Janni / von Minckwitz / Möbus / Müller / Schneeweiss / Simon / Solomeyer / Stickeler / Thomssen Version 2010: Jackisch / Harbeck

3 Adjuvant Chemotherapy without concurrent Trastuzumab: Overview Oxford / AGO LoE / GR Anthracyclines (instead of CMF) 1a A ++ Taxanes (node-positive disease) 1a A ++ Taxanes (node-negative disease) 2b B +/-* Taxanes may be beneficial in N0-patients at high risk of recurrence 2b B + Dose-dense (node-positive disease) 1b B +* CMF (instead of no therapy) 1a A ++ * Study participation recommended

4 FEC / FAC Optimal Combination and Dosage Dosage Oxford / AGO LoE / GR Epirubicin 30 mg/m²/week 1b A ++ Doxorubicin = 20 mg/m²/week 1b A ++ Regimen French: FE 100 C q3w x 6 1b B ++ Canadian: C p.o. E 60 F d1 + 8 q4w x 6 1b B + UK: E 100 q3w x 4 - CMF x 4 1b B + US: FA 60 C q3w x 6 1b B +

5 Phase III Anthracycline Trials

6 Non-Anthracycline Containing Regimens without Trastuzumab* Equivalent OS efficacy to 4 x A / EC: Oxford / AGO LoE / GR 6 x CMF 1a A +/- Superior OS efficacy to 4 x AC : 4 x DC 1b B + *Study participation for non-anthracycline regimens recommended D = Docetaxel; C = Cyclophosphamide; OS = Overall Survival

7 Taxanes Optimal Combination and Dosage Regimen Oxford / AGO LoE / GR DAC D 75 A 50 C q3w x 6 1b B ++ FEC D FE 100 C q3w x 3 D 100 q3w x 3 1b B ++ AC P w * A 60 C q3w x 4 P 80 qw1 x 12 1b B ++ AC D A 60 C q3w x 4 D 100 qw3 x 4 1b a B ++ EC D E 90 C q3w x 4 D 100 qw3 x 4 1b a B ++ * E 90 C P w presumably equieffective

8 Recommended Taxane-Based Regimens Standard Dose Node-positive Combination Treatment Oxford / AGO LoE / GR DAC (BCIRG 001, instead of FAC) 1b B ++ DC (US Oncol., instead of AC) 1b B + AD (E2179, instead of AC) 2b B +/- Sequential Treatment (Equal Duration) FEC D (PACS 01, instead of FEC) 1b B ++ AC Pw (E1199, instead of AC P3w) 1b B ++ FE 60 C D (TACT, instead of FE 60 C) (TACT, instead of E CMF) 2b B - AP CMF (ECTO, instead of A CMF) 2b B + Sequential Treatment (Unequal Duration) AC P (NSABP B-28, instead of AC) 1b B + FEC P (GEICAM 9906, instead of FEC) 2b B + AC D (BCIRG 005, AC-D, instead of DAC) 1b a B ++ EC D (WSG/AGO, EC-D, instead of FEC) 1b a B ++ A D CMF > AD CMF (BIG 2-98, instead of A C CMF) 2b B + E D CMF (TAXIT 216, instead of E CMF 2b B +/- Node-negative* DAC (GEICAM 9805, instead of FAC) 2b a B +/- AP CMF (ECTO, instead of A CMF) 2b B +/- AD (E2179, instead of AC) 2b B - DC (US Oncol., instead of AC) 2b B +/- Only 1 study (PACS 01) demonstrated superiority for OS if compared to adequately dosed anthracycline-based regimen (FEC-D vs FEC; LoE 1b, B). In the sequence AC-Taxane, there is no evidence of superiority of either taxane. Next to substance-specific side-effects, weekly administration was in general less toxic (LoE 2b a, B) A = Doxorubicin, D = Docetaxel; E = Epirubicin; P = Paclitaxel *Study participation recommended

9 Taxanes in Adjuvant Therapy: Overview over Phase III Trials with N>900 (1)

10 Taxanes in Adjuvant Therapy: Overview over Phase III Trials with N>900 (2)

11 Taxanes in Adjuvant Therapy: Meta-Analyses of Phase III Trials with N>900 Trial Source Ind Treatment N (9 trials) Bria 2006 N+/N- T vs no T (13 trials) (12 trials) De Laurentiis 2008 N+/N- T vs no T F/U mo DFS/EFS/RFS/ TTR OS Remarks DFS HR 0.86, p<0.01 N+ DFS HR 0.84, p<0.01 DFS HR 0,83, p<0,00001 Ferguson 2007 N+/N- T vs no T DFS HR 0,81, p<0,00001 HR 0.87, p<0.01 N+ HR 0.84, p<0.01 HR 0,85, p<0,00001 HR 0,81, p<0,00001 no heterogeneity no heterogeneity no heterogeneity (21 trial) Bedard PL 2010 N+/N- T vs no T A, doxorubicin; C, cyclophosphamide; D, docetaxel; DFS, disease-free survival; E, epirubicin; EFS, event-free survival; F, fluorouracil; FFP, freedom from progression; F/U, follow-up; HR, hazard ratio; M, methotrexate; ND, no data; ns, not significat; OS, overall survival; P, paclitaxel; qw, weekly; q3w, three weekly; RFS, relapse-free survival; T, taxane; TTR, time to recurrence; vs, versus. adjuvant part of trial

12 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 - *Study participation recommended P = Paclitaxel; Treatment in experienced centers

13 Dose Density: Overview over Published Phase III Trials with N > 1000

14 High-dose Cx/ABST: Overview over Published Phase III Trials with N > 100

15 Assessment of HER2 Status Oxford LoE: 1b GR: A AGO: ++ Detection of HER2 overexpression is a prerequisite for treatment with trastuzumab Internal and external quality controlled pathology required

16 Adjuvant Treatment with Trastuzumab (1) Oxford / AGO LoE / GR Node-positive disease 2b B ++ Node-negative disease with additional risk factors (e.g. 1 cm) 2b B ++ Node-negative disease with tumors 5 mm and additional risk factors (whenever chemotherapy is considered as adequate) 4 C +* *Study participation recommended

17 Increasing Evidence Suggests that HER2-Positivity is a Negative Prognostic Factor even in Patients with Small (< 1 cm) Node-negative Tumors

18 Adjuvant Treatment with Trastuzumab (2) Start of treatment Simultaneously with taxanes 2b B ++ Sequentially up to 3 months after chemotherapy 2b B + Duration Oxford / AGO LoE / GR For 1 year 2b B ++ For 2 years 2b B - - Dosage 2 (4*) mg/kg every week 2b B ++ 6 (8*) mg/kg every 3 weeks 2b B ++ * Loading dose *Loading dose

19 Trastuzumab in Early Breast Cancer: Overview over Published Phase III Trials Trial Source Ind Treatment N NSABP B31/ NCCTG 9831 Perez 2007 HERA Smith 2006 BCIRG 006 FinHer PACS-04 Metaanalysi s 5 trials Slamon 2006 Joensuu 2009 Spielmann 2007 Viani 2007 IHC 3+ or FISH+ Her2 IHC 3+ or FISH+ Her2 FISH+ Her2 FISH+ IHC 3+ or FISH+ IHC 3+ or FISH+ 4xA 60C 4xP 175Tras Tras 1y vs 4xA 60C 4xP 175 any Cx Tras 1y vs no Tras 4xA 60C 4xD 100Tras Tras 1y vs 6xCb(Cis)D 75Tras Tras 1y vs 4xA 60C 4xD 100 3xD 100Tras or 8xVTras 3xFEC vs 3xD 100 or 8xV 3xFEC 6 X FE 100C vs 6 x Epi 75/D 75 Tras 1y vs. no Tras F/U mo nd R 232 2ndR DFS OS Remarks HR 0.49, p< HR 0.64, p<0.01 Tras vs no Tras p<0.01; A vs no A ns HR 0.42, p=0.01 HR 0,86, p=0,41 HR 0.63, p= HR 0.66, p=0.012 Tras vs no Tras p<0.01; A vs no A ns HR 0.55, p=0.09 HR 1,27 see above 9117 p< p< pooled analysis fewer CHF with CbDTras than AC- DTras subgroup subgroup 30% of pts. Trastuzumab treatment < 1y A, doxorubicin; C, cyclophosphamide; Cb, carboplatin; CHF, congestive heart failure; Cis, cisplatin; Cx, chemotherapy; D, docetaxel; DFS, disease-free survival; E, epirubicin; F, fluorouracil; FISH, fluorescent in situ hybridication; F/U, follow-up; HR, hazard ratio; IHC, immunohistochemistry; ns, not significat; OS, overall survival; P, paclitaxel; Tras, trastuzumab; V, vinorelbine; vs, versus.

20 Adjuvant Trastuzumab Cardiac Monitoring for CHF Oxford LoE: 5 GR: D AGO: ++ Before start of trastuzumab Physical examination (edema, hepatomegaly) Echocardiography (alternative to MUGA) Assessment of LVEF During trastuzumab Regular assessment of Heart rate increase > 15% above individual base level Body weight increase 2 kg/week 3 monthly assessment of LVEF

21 Adjuvant Treatment with Trastuzumab: Schedules Simultaneously Oxford / AGO LoE / GR with paclitaxel / docetaxel after AC / EC 1b B ++ with docetaxel and carboplatin 1b a B + with anthracyclines 2b B +/- with taxanes dose-dense 2b B +/- with taxanes in other regimes 3b a B +/- Radiotherapy concurrent with Trastuzumab 2b B +