Optimal chemotherapy regimen. for older women with breast cancer

Transcription

1 Optimal chemotherapy regimen and targeted treatments for older women with breast cancer Etienne Brain, MD, PhD Medical Oncology HÔPITAL RENÉ HUGUENIN Au 1 er janvier 2010, le Centre René Huguenin devient l Hôpital RenéHuguenin, un établissement de soins, d enseignement et de recherche de l Institut Curie

2 Disclosures Research Support/P.I. Cephalon, Amgen, Ipsogen Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Cephalon, Roche, Janssen, GSK, Amgen Cephalon, Roche, Janssen, Amgen

3 Physiological variations x PK & PD Mechanism Absorption Metabolism Gastric dumping and secretions Hepatocytes, blood flow, CYP P450 activity Interactions (CYP P450) Consequences Absorption of proteins, vitamins and drugs Protein synthesis, (de-) activation of drugs and carcinogens Distribution H 2 O, albumin, Hb Vd hydrosolubles drugs Vd liposolubles drugs Excretion GFR, tubular filtration Biliary excretion Renal elimination of drugs excreted by kidney Biliary elimination Balducci. Oncologist 2000; Wildiers. Clin Pharmacokinet 2003;

4 Chemotherapy Specific doses and monotherapy CMF: CPA dosage and creatinine clearance Capecitabine 1000 mg/m² x 2/D Paclitaxel < 80 mg/m² qw Docetaxel: similar PK but increase risk for neutropenia ± febrile neutropenia > 65 yo q3w 75 mg/m² 63% and 16% vs 30% and 0% qw q2w 35 mg/m² > 50% grade 3 (RD: 26 mg/m²) 50 mg/m² GERICO-04 Gelman J Clin Oncol 1984, Crivellari J Clin Oncol 2000 Bajetta J Clin Oncol 2005, Del Mastro Ann Oncol 2005 ten Tije J Clin Oncol 2005

5 Chemo works in adjuvant if you are careful w/ side effects

6 Adjuvant chemo for breast cancer All DFS CALGB ( ) 4 randomized trials pts > 65 yo 542 (8%) > 70 yo 159 (2%) OS All 50 Results Benefit identical Toxicity careful!! Toxic deaths 1.5% Muss, JAMA 2005

7 Doxorubicin, CHF and age SEER : 43,338 women years, no CHF history stage I to III BC, chemotherapy vs no AC: younger, fewer comorbidities, advanced (p=.001) CHF 10 years (%) AC N = 4,712 Other chemo N = 3,921 No chemo N = 34, years HR 1.26 (95% CI, ) if AC years no impact of CT type Baseline HR (95%CI) Age (decade) 1.79 ( ) Black 1.40 ( ) Trastuzumab 1.46 ( ) Hypertension 1.45 ( ) Diabetes 1.74 ( ) Coronary 1.58 ( ) Left XRT 1.04 ( ) Pinder. J Clin Oncol 2007

8 but mostly in ER- cases!

9 Adjuvant chemotherapy and mortality No. total Giordano* I-III, ER, ,390 Elkin I-III, ER-, 66+ 5,081 No. w/ct 4,500 1,711 pn ER HR (95% IC) HR (95% IC) pn ( ) NA pn ( ) NA both - NA 0.85 ( ) pn ( ) 0.76 ( ) pn+ > 70 yo ( ) *: BC specific mortality Adjuvant chemo is useful FIRST in ER-, pn0 or pn+, even > 70 yo Giordano & Elkin. J Clin Oncol 2006

10 CALGB / CTSU (AC or CMF vs X) DFS OS All ER+ ER- Muss, NEJM 2009

11 We may try to avoid the risk of cardiotoxicity induced by anthracyclines: TC & liposomal doxorubicin

12 Fig 1. Disease-free survival (DFS) and overall survival (OS) (A) DFS by treatment; (B) DFS by treatment and age; (C) OS by treatment: 1 day; (D) OS by treatment and age Jones, S. et al. J Clin Oncol; 27: Copyright American Society of Clinical Oncology

13 GERICO 06 (EUDRACT N , PHRC national 2005) MC MC MC MC XRT q3w q3w q3w trastuzumab if HER2+ ± trastuzumab if HER2+++ CGA ADL + MNA + MMS + GDS + CIRSG QLQ-C30 Willingness ADL Tolerance ADL Tolerance ADL Tolerance CGA ADL + MNA + MMS + GDS + CIRSG QLQ-C30 Willingness Tolerance CGA ADL + MNA + MMS + GDS + CIRSG QLQ-C30 Willingness Tolerance 4 cycles of AC-like chemo In MC, M stands for liposomal non pegylated doxorubicin 1 & 2 year DFS & OS

14 1. Febrile neutropenia 15% favouring primary prophylaxis w/ G-CSF 2. Risk of denutrition increased: 15% at baseline vs 38% after 4 cyles of chemo 3. Impact on QoL (social & role functioning) 4. Good tolerance of trastuzumab when indicated

15 National French Recommendations for Chemotherapy Summary of previous recommendations Validated regimens 4 AC 6 CMF Options: TC 4 TC > 4 AC Post hoc sub group analysis in a randomized trial, n ~ 80 Sequential regimen No data Reassuring data for safety profile of TC grade B MC (liposomal doxorubicin) grade C Systematically discuss primary prophylaxis w/ GCSF expert agreement

16 Targeted treatments Lack of specific data! But clinical evidence for benefit

17 Trastuzumab > 60 yo 16% Piccart NEJM 2005

18 The incidence of CHF from the Finnish Herceptin Study (FINHER), Herceptin Adjuvant trial (HERA), Breast Cancer International Collaborative Group trial 006 (006) with TCH and AC-TH analyzed separately, the North Central Cancer Treatment Group trial 9831 (N9831), and NSABP B-31 (B-31). Bird B R H, Swain S M Clin Cancer Res 2008;14:14-24 NSABP B31 Age 2% < 50 yo vs 5.4% > 60 yo LVEF > 4 AC 12% if LVEF < 55% Concomitant > sequential Hypertension comedications B31/N % pts who had completed AC had a lower LVEF or developed cardiac symptoms preventing the initiation of TZT 1/3 pts who started TZT discontinued it: 4.7% with symptomatic CHF, 14.2% with confirmed asymptomatic decline in LVEF, and the rest for noncardiac reasons 2008 by American Association for Cancer Research

19 No significant decrease of LVEF - post CT - post TZT Only 1 pt w/ significant LVEF decrease post CT who recovered at 1 yr Only 1 pt w/ significant LVEF decrease post TZT (decrease started under chemo), lingering No clinical symptoms Debled, ESMO 2010

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21 Adjuvant setting and trastuzumab No objection when chemo is decided In favour of regimen without anthracyclines docetaxel cyclophosphamide TC + H docetaxel carboplatin TCb + H (BCIRG 06) Anthracylines liposomal formulations? (MC) Slamon, NEJM 2011

22 "Anti-HER2 match" trastuzumab lapatinib

23 Pertuzumab T-DM1 HER3 HER2 dimer DM1 HER2 Trastuzumab P = recombinant humanized mab, prevents dimerization of HER2 with other HER receptors (HER3, HER1, and HER4) (different HER2 epitope than TZT) TZT and P complementary mechanisms of action: broader blockade of the HER tumour cell proliferation and survival signalling P+TZT: CB 50% w/good tolerance (only noted grade 3-4 was diarrhea 3%; asthenia 2%, rash 3%, pruritus 2%), NEOSPHERE TDM1 = µtubule blocking agent DM1 bound to TZT = targeted delivery of DM1 Significant single agent activity in pretreated HER2+ MBC (RR 30-50%) Good tolerance (moderate Plt)

24 L1 Pertuzumab + TZT Pertuzumab + TZT + metronomic CPA TDM-1 at progression Phase IIR, 80 pts /8 IADL or 2/6 ADL or Charlson CS > /8 IADL or 1/6 ADL or Charlson CS > 2

25 Bevacizumab MBC L1 > 65 yo 20% Miller N Engl J Med 2007

26 ATE and bevacizumab ATE events Chemo only Chemo + beva N = 782 N = 963 Global No risk factor < 65 yo yo (N = 279) Previous history of ATE yo and previous history Scappaticci. J Natl Cancer Inst 2007

27 ATHENA: CT wo/anthracyclines + beva % < N = 2018 N = 233* HTN grade Proteinuria grade ATE (A or V) Stop for toxicity ATE CHF HTN *175 (7.8%) 70+, 51 (2.3%) 75+, 7 (0.3%) 80+ Biganzoli. Annals Oncol 2011

28 What is the crux?

29 Competing causes of mortality Cumulative probability of death Breast NHL Cumulative probability of death vs attained age Competing HR of death Deaths attributed to the primary cancer (solid dots) and those attributed to comorbidity (open circles) Kendal. Cancer 2008

30 General recommendations for elderly BC pts Special attention to AEs Evaluation of CrCl (Cockroft and MDRD) mandatory Cognitive status, depression, anxiety, social settings: can influence patient decisions Multiple medications (+ OTC and alternative medicines): frequent, drug-drug interactions+++ High risk of poor compliance (living alone or with cognitive impairment) Underestimation of true prevalence Close monitoring to allow prompt intervention Atypical presentations Concomitant medications Use of G-CSF and ESA (but careful with anti-vegf) Expectations may vary considerably in terms of disease outcomes, benefits from therapy and must be considered in joint decision making