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A clinical challenge: integrating all agents

A clinical challenge: integrating all agents. Edith A Perez, MD Mayo Clinic Jacksonville, Florida, USA Introduction by Christoph Zielinski University Hospital Vienna, Vienna, Austria. Case history. 49-year-old woman: 1.4cm lesion in the left breast Lumpectomy and axillary lymphadenectomy

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A clinical challenge: integrating all agents

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  1. A clinical challenge: integrating all agents Edith A Perez, MD Mayo ClinicJacksonville, Florida, USA Introduction byChristoph ZielinskiUniversity Hospital Vienna, Vienna, Austria

  2. Case history • 49-year-old woman: 1.4cm lesion in the left breast • Lumpectomy and axillary lymphadenectomy • Poorly differentiated, infiltrating ductal carcinoma • grade 3 • ER/PR negative • HER2 IHC 1+ (negative) • Three positive axillary nodes of 29 examined • Social history: three young children

  3. Clinical course • Adjuvant therapy with dose-dense doxorubicin/cyclophosphamide followed by paclitaxel • Relapsed with multiple metastases in liver, lung and bone within 1.5 years • Abdominal and low level bone pain • several small spinal spots • several bilateral rib lesions • back pain high thorax

  4. Anthracyclines or single-agent taxanes not optimal for this patient • Anthracyclines • frequently used in adjuvant • re-use in metastatic not always possible, or justified, due to • cumulative cardiotoxicity • Taxanes • have been gold standard • combination preferable to single-agent • Xeloda added to Taxotere improves survival

  5. Other single-agent options • Vinorelbine • varying response rates; lack of randomized data • Gemcitabine • varying response rates; lack of randomized data • Xeloda • comparable efficacy versus CMF or paclitaxel • favorable safety profile and convenient

  6. Combination anthracycline/taxane no better than sequence • ECOG study E1193 in first-line MBC compared • doxorubicin plus paclitaxel (AP) • doxorubicin paclitaxel • paclitaxel doxorubicin • AP versus sequential single agents • better disease control • better time to progression • no change in survival or QoL Sledge G et al. J Clin Oncol 2003;21:588–92

  7. Combination XT superior survival versus T X Beslija1 O’Shaughnessy2 • All endpoints statistically significant difference 1Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407) 2O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23

  8. Avastin plus paclitaxel significantly improves efficacy versus paclitaxel alone • First-line Avastin plus paclitaxel (n=350) versus paclitaxel alone (n=332) • response rate: 29.9 vs 13.8%, p<0.0001 • 5-month PFS improvement • 11.4 vs 6.11 months • HR=0.51; p<0.0001 Miller KD et al. Breast Cancer Res Treat 2005;94:S6 (Abst 3)

  9. Non-overlapping toxicity when Avastin is added to paclitaxel Miller KD et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S6 (Abst 3)

  10. Recent evidence for Avastin plus docetaxel • Phase II trial (first-/second-line MBC) • Analysis of efficacy in first 13 patients • 7 partial responses (54%) • 4 stable disease (31%) • Acceptable toxicity • few grade 3/4 adverse events attributable to Avastin in therapeutic regimen Ramaswamy B et al. Breast Cancer Res Treat 2003;81:S50 (Abst 224)

  11. Phase III Xeloda versus Xeloda/Avastinin A/T-pretreated MBC • 3-weekly regimen • Xeloda 1250mg/m2 twice daily, days 1–14 • Avastin 15mg/kg, day 1 A/T = anthracycline/taxane Miller K et al. J Clin Oncol 2005;23:792–9

  12. Xeloda/Avastin: minimal added toxicity Miller K et al. J Clin Oncol 2005;23:792–9

  13. Progression of angiogenic activity in human breast tumors Tumor growth VEGF VEGF bFGF TGF-1 VEGF bFGF TGF-1 PlGF VEGF bFGF TGF-1 PlGF PD-ECGF VEGF bFGF TGF-1 PlGF PD-ECGF Pleiotrophin VEGF = vascular endothelial growth factorbFGF = basic fibroblast growth factorTGF-1 = transforming growth factor beta-1PlGF = placental growth factorPD-ECGF = platelet-derived endothelial cell growth factor Relf M et al. Cancer Res 1997;57:963–9

  14. Considerations for the addition of Avastin to chemotherapy in this patient • Anti-angiogenic therapy has biological and clinical merits in first line • non-overlapping toxicities with chemotherapy • Addition of Xeloda to Taxotere (XT) extends survival • Adding Avastin to paclitaxel significantly improves response and PFS • Combination of Avastin with XT may furtherimprove outcomes

  15. Antitumor activity of Xelodacombined with Avastin Mean tumor volume (mm3) 1000 800 600 400 200 0 KPL4 ER– xenograft Control X ½ MTD X MTD A A + X ½ MTD A + X MTD 14 16 18 20 22 24 26 28 30 32 Days post-tumor cell implant

  16. Recommendation for the treatment of this patient • Consider the patient’s characteristics • relatively young: only 49 years at first diagnosis; 51 years at relapse to metastatic disease • adjuvant anthracyclines/paclitaxel • reasonably fit (ECOG PS = 1) • fast-progressing, aggressive disease • Clinical trial with Xeloda/Taxotere/Avastin (XTA)is an attractive option for this patient • XTA trial (NCCTG 0432; PI Edith Perez) is ongoing

  17. 1 8 15 21 Days 1–14 Rest NCCTG 0432: phase II trial of first-line Xeloda/Taxotere/Avastin (n=46) • Some other studies use X900T60 Day Taxotere75mg/m2 Avastin 15mg/kg Repeat cycle at day 22 Xeloda825mg/m2twice daily (oral) Unpublished data courtesy of Dr E Perez

  18. N0432: baseline characteristics (n=46) Unpublished data courtesy of Dr E Perez

  19. XTA: low incidence of non-hematologic grade 3/4 adverse events Patients (%) 80 70 60 50 40 30 20 10 0 HFS Rash Fatigue Nausea Diarrhea Vomiting Stomatitis Febrileneutropenia Neuromotor Leucopenia Neutropenia Unpublished data courtesy of Dr E Perez

  20. Why choose oral Bondronat? • Convenience of oral dosing instead of i.v. • Oral Bondronat has comparable bone marker efficacy to i.v. zoledronic acid • Oral Bondronat controls and maintains bone pain significantly below baseline levels

  21. Clinical course continued • Chemotherapy interrupted (Avastin continued), diarrhea rapidly resolved • Cycle 3 XT restarted at same doses, as planned • patient education important • prescription for loperamide • Symptoms (bone pain) fully resolved by endof cycle 3

  22. Clinical course continued • Patient maintained on Xeloda/Avastin only • Bondronat continued • After 18 months • partial response maintained • symptom free • occasional grade 1 hand-foot syndrome managed with treatment interruption

  23. Therapy with Xeloda and Avastin should be continued until disease progression • Oral Xeloda • effective with demonstrated use for up to 5 years • favorable safety profile, minimal myelosuppression and alopecia • common side effects easily managed • Avastin • use until disease progression strongly supported by mechanism of action • demonstrates benefit when used until progression in clinical trials • is well tolerated; most common side effects are mild and easily manageable

  24. Addressing a clinical challenge in MBC • Appropriate doses of Xeloda and taxane allow patients to • reap the benefits of this active combination • receive a well-tolerated treatment • Adding Avastin to XT should further improve outcomes, with minimal added toxicity • Bondronat offers skeletal related events efficacy and outstanding bone pain relief without renal safety complications

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