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Highlights in the Management of Breast Cancer

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  1. CINBO Consorzio Interuniversitario Nazionale per la Bio-Oncologia Highlights in theManagement of Breast Cancer “Taxanes vs Anthra-containing chemotherapy in the treatment of early-BC and the issue of cardiac toxicity” Rome, May 25-26, 2007 Vincenzo Adamo Oncologia Medica e Terapie Integrate A.O.Universitaria, Policlinico “G. Martino” Messina

  2. from Lancet ‘98 to Oxford 2000

  3. CMF and node positive Patients RFS HR 0.71, p.005 OS HR 0.79, p.04 Median Follow up 28.5 yrs G. Bonadonna,BMJ, Jan 2005

  4. Crown J. Ed. Book, ASCO 2004

  5. EBCTCG OVERVIEW 2005 AND ISSUE SYSTEMIC CHEMOTHERAPY TO CONFIRM • To need of adjuvant chemotherapy for early breast cancer • A superiority of antrhaciclynes based regimens in adjuvant setting The Lancet Vol 365 May 14, 2005

  6. Single-Agent Chemotherapy vs Not and Polychemotherapy vs Not from the EBCTCG (2005)

  7. Anthravs otherregimens 5 yr of recurrence from the EBCTCG (2005)

  8. Which Anthracycline-basedregimen ? • Three-drug regimens • CAF>CMF ± Tam(INT 0102) • CEF>CMF(NCIC-CTG) • Sequential regimen • E  CMF > CMF(NEAT-SCTBG BR9601) • Two-drug regimens • AC = CMF TAM(NSABP B-15, B-23) • EC and hEC = CMF(Belgian trial)

  9. ROLE OF TAXANES IN ADJUVANT SETTING “Taxanes (Paclitaxel and Docetaxel) with significant antitumoral activity in metastatic disease have been evaluated in the adjuvant setting, and their inclusion can further modify the natural history of the disease by reducing the risk of recurrence and death” Buzdar AU, et al. editorial JCO2007

  10. ROLE OF TAXANES IN ADJUVANT SETTING • First GenerationTrials: 31000 pts • Comparing taxane/anthracycline to non-taxane/anthracycline • Sequential (anthra followed by taxane) • Combination • Second GenerationTrials: 25000 pts • Comparing taxanes in both arms • Sequential • Combination • With Herceptin Nowak AK et al. Lancet Oncol 5: 372–80, 2004

  11. Randomized Trials of Adjuvant Chemotherapy with Taxanes

  12. NSABP B28 N= 3060 N+ pts P 225mg/m2(3 h) C 600 mg/m2 NONE A 60 mg/m2 Recommended TAM if HR(+) with chemoRx Median follow-up 64.8-64.4 months Mamounas et alJCO 2005

  13. NSABP B28: Toxicity *cardiac dysfunction either during or subsequent to therapy °acute myelogenous leukemia ormyelodysplastic syndrome **AC: pulmonary embolism in one, congestive heart failure in two, sepsis in one, and seizure in one; AC and PTX: coronary artery disease in one, pulmonary embolism in one.

  14. CALGB 9344 RR: recurrence 17% N= 3121 N+ pts P 175 mg/m2(3 h) C 600 mg/m2 RR: death 18% RR:death18% NONE A 60= 75= 90 mg/m2 Recommended TAM if HR(+) after chemoRx Median follow-up 69.0 months Henderson et alJCO 2003

  15. CALGB 9344: Toxicity There was no difference in incidence of cardiotoxicity between those who did and those who did not receive paclitaxel. CHF was observed during active protocol therapy in four (<1%) and six (<1%) pts and during post treatment follow-up in 23 (1%) and 27 (2%) pts randomly assigned to CA alone and CA plus paclitaxel, respectively. °including high dose of Doxorubicin

  16. E2197 Trial Goldstein L,PASCO ’05 abs 512

  17. E2197:Results I Goldstein L, PASCO ’05 abs 512

  18. E2197:Results II Goldstein L, PASCO ’05 abs 512

  19. E2197: Toxicity Goldstein L,PASCO ’05 abs 512

  20. BCIRG001 Adaptated 26° SABCS 2003

  21. BCIRG001: post Chemotherapy Treatment Adaptated 26° SABCS 2003

  22. BCIRG001: characteristics of the pts and the tumors Martin M et al N Engl J Med 352; 22, 2, 2005

  23. Analysis of Survival Rates in the two Study Groups Martin M et al N Engl J Med 352; 22, 2, 2005

  24. Risk Reduction for Disease-free Survival in the Main Subgroups Martin M et al N Engl J Med 352; 22, 2, 2005

  25. BCIRG001: toxicity Martin M et al N Engl J Med 352; 22, 2, 2005

  26. MDACC TRIAL Buzdar AU, et al. Clinical Cancer Research 2002

  27. MDACC TRIAL: Results ER- pts RFS all pts ER+ pts Buzdar AU etal, Clinical Cancer Research 2002

  28. MDACC TRIAL: toxicity Buzdar AU, et al. Clinical Cancer Research 2002

  29. PACS-01 Stratified on: Center  Age: < or  50  N: 1-3;  4 6 FEC-100: ARM A Fluorouracil 500 mg/m² d1 Epirubicin 100 mg/m² d1 Cyclophosphamide 500 mg/m² d1 6 cycles every 21 days S U R G E R Y R 3 FEC-100/3 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 womenafter chemotherapy

  30. PACS-01:characteristics of pts and tumors Roché H et al J Clin Oncol 2006

  31. PACS-01: RESULTS DFS OS Roché H et al J Clin Oncol 2006

  32. PACS-01: DFS in different subgroups(Forest plot analysis) Roché H et al J Clin Oncol 2006

  33. PACS-01:Toxicity Roché H et al J Clin Oncol 2006

  34. ECTO Study Gianni L, et al, Clin Cancer Res 2005

  35. Patient characteristics and results Gianni L, et al. Clin Cancer Res 2005

  36. Main toxicities Gianni L, et al. Clin Cancer Res 2005

  37. NCIC CTG MA.21 q 3 w Pts N+ or N- HRisk q 3 w q 2 w Primary end point: relapse free survival (RFS) Secondary end-points: overall survival, toxicity and QoL Burnell M et al. Breast Cancer Res Treat. Abs 53, 2006

  38. NCIC CTG MA.21: Schedules CEF = oral cyclophosphamide/epirubicin/5-fluorouracil; AC-T =doxorubicin/cyclophosphamide and paclitaxel; EC-T = epirubicin/cyclophosphamide and paclitaxel; from medscape: Update on Adjuvant Chemotherapy in BC H McArthur & C Hudis, 2007   

  39. NCIC CTG MA.21: Results 2104 patients enrolled Dec-2000-April 2005 global test of significance

  40. NCIC CTG MA.21 However, both the CEF and dose-dense EC-T regimens were associated with increased rates of febrile neutropenia,TVE, and delayed cardiotoxicity compared with AC-T.

  41. Randomized Trials of Adjuvant Chemotherapy with Taxanes * parameter after 4 years of follow up

  42. Cardiac Toxicity P=0.09 P=1.0 During and posttreat P=.03 P=.63 P=.09

  43. Comments • Cardiac toxicity data are controversial: most of the trials don’t include a careful cardiac monitoring before, during and after the treatments • Many trials demostrate that Anthracyclines and Taxanes are the most active cytotoxic drugs for the treatment of breast cancer also as adjuvant chemotherapy. • However the advantages obtained by this combination must be carefully balanced against potential risks, particularly in the adjuvant setting.

  44. Mechanisms and types of Cardiotoxicity Associated with different therapeutic modalities by Brian R, et al, Ed Boock ASCO 2007

  45. Who need Adjuvant Chemotherapy ?

  46. Adjuvant Chemotherapy Options Trastuzumab if HER-2 positive adapted fromPiccart et al. (2005)

  47. Anthracyclines may not be necessary in adjuvant therapy of breast cancer ?

  48. Slamon SABCS 2006

  49. Slamon “BCIRG 006”, SABCS 2006