Common disease 175,000 new cases/year 44,000 deaths/year Less than 10% with newly diagnosed at presentation have stage IV disease Chronic disease,

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1 Chemotherapy for Metastatic Breast Cancer: Recent Results HARMESH R. NAIK, MD. Karmanos Cancer Institute and St. Mary Hospital

2 Metastatic breast cancer (MBC) Common disease 175,000 new cases/year 44,000 deaths/year Less than 10% with newly diagnosed at presentation have stage IV disease Chronic disease, considered incurable Heterogeneous group of patients

3 General approach to MBC Diagnostic work-up Determine goals Initial treatment Monitoring Change the treatment Know when to

4 Diagnostic work-up Physical examination Organ assessment by symptoms Asses bone, liver, lungs and brain ER/PR and HER-2-Neu status Cardiac function (MUGA scan)?? Tumor markers Available support system

5 Specific goals for MBC Estimating prognosis and response Management and prophylaxis of complications Promoting physical and psycho-social well being (quality of life) Prolonging survival End of life decisions

6 Estimation of prognosis Important first step SEER data Median survival: 18 months 5 year survival: 13% CALGB data Median survival: 18 months 3 year survival 26%

7 Is long term survival possible? Yes : The M. D. Anderson data 1581 patients treated with Dox based chemo 263 (16.6%) CR 49 (3.1%) continued CR at 5 years 26 (1.6%) CR at median follow-up of 191 months Younger age, good PS, few sites and low tumor burden: good indicators

8 Prognostic factors Prior adjuvant therapy Liver metastases Negative Estrogen receptors All of above: 0% 3 yr survival with median survival of 6 months None of above: 50% 3 yr survival

9 Prognosis Survival and poor prognostic factors % all none 3 year survival in MBC (CALGB)

10 Other important factors Performance status Organ function (heart, kidneys, liver) Co-morbid conditions?her-2-neu status Prior therapy Disease free interval Sites of metastases

11 Efficacy of Docetaxel in MBC based on prior therapy no prior >1 prior A resistant reponse

12 Effect of sites of mets on median survival 25 months m e d s u r v bone soft tissue lung liver brain site of metastases

13 Initial therapy for MBC Metastatic disease Limited mets Good PS ER/PR +ve visceral mets extensive mets ER/PR neg hormonal failure HORMONAL THERAPY CYTOTOXIC CHEMOTHERAPY

14 Potential outcomes of treatment PD PD size SD PR CR Time Treatment

15 Disease course size first line second third fourth Treatment

16 How long? How much? FIRST LINE SECOND LINE?THIRD LINE??FOURTH LINE STOP

17 Effect of prior therapy on efficacy of Pac on MBC response no ch 1 prior 2 prior >3 prior

18 Current questions Single vs Combinations Old vs new Combination vs combinations A vs non-a High dose vs standard dose Chemo-hormonal vs chemotherapy

19 Single agents Doxorubicin 43% Cyclophosphamide 36% 5 FU 28% Paclitaxel 36-62% Docetaxel 52-68% Vinorelbine 40-52% Capecitabine 24%

20 Potential combinations

21 Putting the puzzle together

22 Commonly used regimens CMF type FAC or CAF or AC: Dox based Mito + Velban 5 FU based regimens Doxorubicin-Paclitaxel Doxorubicin-Docetaxel Herceptin-Paclitaxel

23 Overview of chemotherapy comparision resposes Poly vs monotherapy 48 vs 34% A vs non-a 51 vs 45 Other CT vs CMF 49 vs 44 Epirubicin vs A 44 vs 47 High vs low intensity 44 vs 33

24 First line chemotherapy 45-75% overall responses Duration of remission: 6-12 mo 10% or less have complete remission Choice of regimens Monotherapy vs combinations CMF: 40-60% RR, FAC: 40-80% RR Metanalysis: Dox better than CMF

25 New vs old regimens Pac vs CMFP Same responses (NS) Better Med Sur with Paclitaxel Pac treatment was 15 independent 10 prognostic factor for 5 survival 0 RR med sur Pac CMFP

26 Doc vs Dox Randomized trial Better RR with Doc Same med survival Dox has more febrile neutropenia RR CR TTPwk Doc Dox

27 Pac vs Dox EORTC trial Crossover design Not equitoxic doses Dox more toxic but had better RR and PFS PR CR PFS-m Pac Dox

28 Taxane-Anthracycline combinations (Phase II trials) High overall RR: 42-93% High complete remissions: 4-41% High initial cardiac toxicity Limit Dox dose 360 mg/m 2?Less cardiotoxicity with Docetaxel Awaiting ongoing randomized trials

29 ECOG 1193 (A vs T vs AT) Frontline, randomized large trial Cross over allowed Same med survival and OS in all 3 arms Same med survival as past major trials Better RR and TTF with Paclitaxel Is combination really superior?

30 Monotherapy vs combination: ECOG 1193 Variable Dox Pac D+P# RR 36% 34% 47% CR 6% 3% 9% TTF(mos) Survival 18.9m 22.2m 22m(NS) Cardiotox. 9% 4% 9% #requires G-CSF

31 AT vs AC (Firstline) in MBC Doc-Dox vs Dox-Cyt Large multicenter trial Higher RR and CR with AT Longer TTP with AT Awaiting overall survival more neutropenic fever with AT No excess cardiotoxicity

32 AT vs AC Variable AT AC No Response rate 60% 47% CR 11% 8% TTP 37.1 wks 31.9 wks (SS) Neutro. Fever 33% 6% CHF 2% 4%

33 Salvage therapy Worthwhile for many Second and third-line therapies Up to 20% response rates for third line Individualize the treatments Palliative goals only Balance side effects with any benefits

34 Anthracycline resistant breast cancer A significant problem Overall survival < 6 months RR: < 10% Taxanes: 30-40% RR, survival: mo Herceptin: 16% RR Prognosis improving with new agents

35 New vs old regimens Doc vs Mito+Vel 30 Anthracycline refractory Doc has better RR, time to progression and survival 1 yr surv: 50% vs 33% RR TTP wks Med sur-m Doc M+V

36 Anthracycline and Paclitaxel refractory MBC Less studies approach 0-27% responses Docetaxel: 18% RR Vinorelbine: 0-27% 5 FU (CI): 12% Diff Paclitaxel schedule: 20-27% Oral Capecitabine: 20-24%

37 When to stop the treatment Multiple decision points When goals of therapy are met Intolerable side-effects Art as well as a science

38 What s new in future? Different sequencing Different schedules Newer drugs Newer combinations Biological therapies Higher dose intensity Targeted therapy

Nadia Harbeck Breast Center University of Cologne, Germany

Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings Nadia Harbeck Breast Center University of Cologne, Germany Evidence in Favor of Taxane Based Combinations