Chemotherapy for Metastatic Breast Cancer: Recent Results HARMESH R. NAIK, MD. Karmanos Cancer Institute and St. Mary Hospital
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
General approach to MBC Diagnostic work-up Determine goals Initial treatment Monitoring Change the treatment Know when to
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
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
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%
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
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
Prognosis Survival and poor prognostic factors % 50 40 30 20 10 0 all none 3 year survival in MBC (CALGB)
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
Efficacy of Docetaxel in MBC based on prior therapy 60 55 50 45 40 35 30 25 20 no prior >1 prior A resistant reponse
Effect of sites of mets on median survival 25 months m e d s u r v 20 15 10 5 0 bone soft tissue lung liver brain site of metastases
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
Potential outcomes of treatment PD PD size SD PR CR Time Treatment
Disease course size first line second third fourth Treatment
How long? How much? FIRST LINE SECOND LINE?THIRD LINE??FOURTH LINE STOP
Effect of prior therapy on efficacy of Pac on MBC 70 60 50 40 30 response 20 10 0 no ch 1 prior 2 prior >3 prior
Current questions Single vs Combinations Old vs new Combination vs combinations A vs non-a High dose vs standard dose Chemo-hormonal vs chemotherapy
Single agents Doxorubicin 43% Cyclophosphamide 36% 5 FU 28% Paclitaxel 36-62% Docetaxel 52-68% Vinorelbine 40-52% Capecitabine 24%
Potential combinations
Putting the puzzle together
Commonly used regimens CMF type FAC or CAF or AC: Dox based Mito + Velban 5 FU based regimens Doxorubicin-Paclitaxel Doxorubicin-Docetaxel Herceptin-Paclitaxel
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
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
New vs old regimens Pac vs CMFP Same responses (NS) Better Med Sur with Paclitaxel 35 30 25 20 Pac treatment was 15 independent 10 prognostic factor for 5 survival 0 RR med sur Pac CMFP
Doc vs Dox Randomized trial Better RR with Doc Same med survival Dox has more febrile neutropenia 50 45 40 35 30 25 20 15 10 5 0 RR CR TTPwk Doc Dox
Pac vs Dox EORTC trial Crossover design Not equitoxic doses Dox more toxic but had better RR and PFS 45 40 35 30 25 20 15 10 5 0 PR CR PFS-m Pac Dox
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
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?
Monotherapy vs combination: ECOG 1193 Variable Dox Pac D+P# RR 36% 34% 47% CR 6% 3% 9% TTF(mos) 5.9 6 8 Survival 18.9m 22.2m 22m(NS) Cardiotox. 9% 4% 9% #requires G-CSF
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
AT vs AC Variable AT AC No. 213 210 Response rate 60% 47% CR 11% 8% TTP 37.1 wks 31.9 wks (SS) Neutro. Fever 33% 6% CHF 2% 4%
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
Anthracycline resistant breast cancer A significant problem Overall survival < 6 months RR: < 10% Taxanes: 30-40% RR, survival: 10-12 mo Herceptin: 16% RR Prognosis improving with new agents
New vs old regimens Doc vs Mito+Vel 30 Anthracycline refractory 25 20 Doc has better RR, time to progression and survival 1 yr surv: 50% vs 33% 15 10 5 0 RR TTP wks Med sur-m Doc M+V
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%
When to stop the treatment Multiple decision points When goals of therapy are met Intolerable side-effects Art as well as a science
What s new in future? Different sequencing Different schedules Newer drugs Newer combinations Biological therapies Higher dose intensity Targeted therapy