Ma X imizing the benefits of Xeloda in clinical practice

1. MaXimizing the benefits of Xeloda in clinical practice Nadia Harbeck Technical University of MunichMunich, Germany

2. Case history • September 2003 • 63-year-old woman: mass in right breast • core biopsy: malignant cells • Right wide local excision and axillary clearance • 2.2cm, grade 3 invasive ductal carcinoma • lymphatic/vascular invasion • 4/10 lymph nodes involved • ER/PR/HER2 negative • staging investigations negative for metastases

3. Clinical course • October 2003–March 2004: adjuvant chemotherapy • 4 x AC followed by 4 x paclitaxel • treatment complicated by postoperative deep vein thrombosis and depression • Adjuvant radiotherapy • 50Gy to right breast and supraclavicular fossa with 12Gy boost

4. Disease progression • February 8 2005 • abdominal pain, anorexia, lethargy • hepatomegaly • no lymphadenopathy, no evidence of local recurrence • blood test, CT scan and bone scan performed • One week later • jaundiced, liver function significantly abnormal • normal renal function • CT scans: small lung & extensive liver metastases

5. Liver function tests abnormal

8. Clinical course: chemotherapy • Xeloda 1250mg/m2 twice daily, days 1–14 every 21 days • body surface area: 1.42m2 • 7 x 500mg tablets per day • Patient education checklist followed • patients advised on side-effect management upfront with telephone follow-up • interrupt Xeloda immediately for grade 2 toxicities • telephone physician/nurse • begin appropriate treatment: patients should have supportive medications at home

9. Single agent response rates in anthracycline- or taxane-pretreated MBC 1Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8 2Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039) 3Fazeny B et al. Cancer Chemother Pharmacol 1996;39:150–6 4Keller AM et al. J Clin Oncol 2004;22:3893–901 5Udom DI et al. Eur J Cancer 2000;36:177–82 6Smorenburg CH et al. Breast Cancer Res Treat 2001;66:83–7 7Spielmann M et al. Oncology 2001;60:303–7

10. Xeloda: consistently high activity in taxane-pretreated MBC • Xeloda is more effective than other monotherapies, p=0.00562 1Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8 2Miles D et al. Clin Breast Cancer 2004;5:273–8

11. 16 6 7 8 9 10 11 12 13 14 15 Xeloda: superior overall survivalin taxane-pretreated MBC 96-hour continuousinfusion vinorelbine (n=47) Jara-Sanchez et al., 2003 High-dose vinorelbine/G-CSF (n=40) Livingston et al., 1997 Xeloda (n=162) Blum et al., 2001 Xeloda (n=136)Reichardt et al., 2003 Xeloda (n=126) Fumoleau et al., 2004 Weekly vinorelbine (n=40) Zelek et al., 2001 Mediansurvival (months) Xeloda (n=230) Miller et al., 2005 Gemcitabine(n=23) Smorenburg et al., 2000 Taxotere (n=46) Valero et al., 1998 Xeloda (n=74) Blum et al., 2001

12. XT (n=50) T X (n=50) This patient received single-agent Xeloda but could have received XT Survival probability 1.0 0.8 0.6 0.4 0.2 0.0 Hazard ratio = 0.53 p=0.006 19 22 0 5 10 15 20 25 30 35 40 Months Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407)

13. Optimal therapy for metastatic disease • Highly effective • Ultimately prolongs survival • Has minimal toxicity • Maintains quality of life • Has minimal interference with normal lifestyle • is convenient • Reduces tumor-related symptoms

14. Determinants of survival for patients with metastatic disease • Hormone-receptor status • Disease-free interval: disease aggressiveness; responsiveness to therapy; slow- or fast-progressing • Predominant site of metastases and number of metastatic sites • Age • Performance status • Comorbidities • HER2 status Pyrhonen S et al. Breast Cancer Res Treat 1999;56:133–43 Thomas E, Berner G. Eur J Oncol Nurs 2000;4:10–17

15. Hormone-receptor + HER2+ HER2+ HER2– Herceptin ± chemotherapy Tamoxifen Fulvestrant Aromatase inhibitor Ovarian suppression Other factors: Prior adjuvant therapy Disease-free interval Burden and distribution of disease (chemotherapy) Novel targeted agents: Avastin; lapatinib Novel cytotoxic agents: epothilones Treatment algorithm for MBC MBC Hormone-receptor – HER2– Anthracyclines Taxanes Xeloda Vinorelbine Liposomal doxorubicin Gemcitabine Combinations Xeloda

16. Clinical course on Xeloda • Day 13, cycle one • patient returned to clinic (diarrhea) • mild nausea • 3–5 bowel movements/day • LFTs improving • no myelosuppression • Xeloda treatment interrupted • Day 21, cycle one • grade 3 stomatitis • diarrhea resolved

18. Clinical course continued • Stomatitis resolved by day 31 • Xeloda restarted day 33 • 1000mg/m2 twice daily, days 1–14, every 21 days

19. Improving liver function tests during treatment Level LDH ALP GGT ALT AST Bili Week 1 Week 3 Week 5 Week 7 Week 9 Week 11 Week 13 Week 15 Week 17 Week 19 Week 21

20. Efficacy not compromised with dose reduction to 1000mg/m2 • Overall response rate of 26% in 74 taxane-pretreated patients with MBC • dose reduction to 1000mg/m2 in 50% of patients • dose reduction did not impact efficacy in terms of TTP (hazard ratio = 0.918) • Can reassure patients that dose modification will not affect efficacy of treatment Blum JL et al. Cancer 2001;92:1759–68

21. Dose reduction reducesrecurrence of adverse events F. Hoffmann-La Roche, data on file

22. Clinical course continued • Cycles two and three • grade 1 stomatitis for 3 days • no diarrhea • continued improvement in LFTs • CT scans after cycle 3

24. Most liver function tests normalized after seven cycles of Xeloda

26. Clinical course • Maintenance chemotherapy with Xeloda 1000mg/m2 twice daily, days 1–14, every 21 days

27. More cycles of chemotherapy lead to improved survival? More cycles better Fewer cycles better Ejlertson 93 Gregory 97 Coates 87 Harris 90 1.23 (95%CI: 1.09–1.38) combined p=0.01 1.6 2.5 0.4 1.0 0.6 Ratio of median survivals Stockler M et al. Eur J Cancer 1997;33:2147–8

28. Xeloda: a highly effective, flexible treatment option • Consistently high efficacy • Well tolerated • Ideal maintenance treatment