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Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results James Cassidy, MD Colorectal Cancer Update Think Tank.

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Presentation on theme: "Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results James Cassidy, MD Colorectal Cancer Update Think Tank."— Presentation transcript:

1 Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results James Cassidy, MD Colorectal Cancer Update Think Tank Meeting June 24, 2005

2 1° endpoint: Disease-free survival (DFS) 2° endpoints  Relapse-free survival (RFS)  Overall survival  Tolerability (NCIC CTC)  Pharmacoeconomics  QoL Capecitabine 1,250 mg/m 2 twice daily, d1–14, q21d n = 1,004 Bolus 5-FU/LV 5-FU 425 mg/m 2 plus LV 20 mg/m 2, d1–5, q28d n = 983 Recruitment 1998–2001 X-ACT Trial in Adjuvant Treatment of Dukes’ C Colon Cancer Chemo-naïve Dukes’ C, resection ≤8 weeks Source: Cassidy J. Presentation. ASCO 2005.

3 X-ACT Powered to Establish at Least Equivalence of Capecitabine Sample size to achieve  80% power for at least equivalence in DFS  Noninferiority margin 1.25 for hazard ratio of capecitabine vs 5-FU/LV  Analysis in per-protocol and ITT populations Secondary analyses  Test for superiority in DFS, RFS, OS Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

4 Standard Eligibility Criteria Eligible patients  Aged 18–75 years  Histologically confirmed Dukes’ C colon cancer  Fully recovered after surgery  ECOG PS: ≤1  Life expectancy ≥ 5 years Excluded patients  Metastatic disease  Prior cytotoxic chemotherapy or organ allografts  Clinically significant cardiac disease  Severe renal impairment  Central nervous system disorders  Pregnant or lactating women Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

5 Protocol-Defined Populations and Endpoints Populations  Intent to treat, all randomized patients  Per-protocol population excludes major protocol violations and patients with <12 weeks treatment Time-related endpoints  Disease-free survival Relapses or new occurrences of colon cancer and all deaths  Relapse-free survival Relapses/new occurrences of colon cancer and deaths related to treatment or colon cancer  Overall survival Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

6 Bolus 5-FU/LV IV leucovorin 20 mg/m 2 + IV 5-FU 425 mg/m 2 Capecitabine Capecitabine 1,250 mg/m 2 twice daily Day Treatment (days 1–14) Rest (days 15–21) 1 2 3 4 581521 Repeat cycle x 8 (24 weeks) 28 OR Repeat cycle x 6 (24 weeks) X-ACT Treatment Schedules Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

7 X-ACT Treatment Arms Were Well Balanced Capecitabine n = 1,004 (%) Bolus 5-FU/LV n = 983 (%) Age, median (range)62 (25–80)63 (22–82) ECOG 0/185/15 Male/Female54 / 46 Normal CEA8384 T1-210 T376 T414 N 1/270/3071/29 Well differentiated910 Moderately differentiated6563 Poorly differentiated/anaplastic1720 Source: Cassidy J. Presentation. ASCO 2005.

8 Other Prognostic Factors Were Balanced Capecitabine n = 1,004 (%) Bolus 5-FU/LV n = 983 (%) Lymph nodes N17071 N23029 T-stage T1-210 T376 T414 Differentiation well910 moderately6563 poorly1619 anaplastic11 Source: Twelves C. Presentation. ASCO 2005.

9 Median follow-up 51 months Strong Trend to Superior DFS (ITT) 1.0 0.8 0.6 0.4 01234560123456 Years Estimated probability Capecitabine (n = 1,004) 64.6% 5-FU/LV (n = 983) 61% HR = 0.87 (95% CI: 0.75–1.00) p < 0.0001 Source: Twelves C. Presentation. ASCO 2005.

10 Capecitabine versus Bolus 5-FU/LV: Superior Relapse-Free Survival (ITT) Estimated probability Capecitabine (n = 1,004) 5-FU/LV (n = 983) 01234560123456 Years HR = 0.86 (95% CI: 0.74–0.99) p = 0.0407 1.0 0.8 0.6 0.4 Source: Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.

11 Capecitabine Showed Trend to Improved Overall Survival (ITT) Estimated probability Capecitabine (n = 1, 004) 81.7% 5-FU/LV (n = 983) 78.3% 01234560123456 Years HR = 0.89 (95% CI: 0.74–1.07) p < 0.001 1.0 0.8 0.6 0.4 Source: Cassidy J. Presentation. ASCO 2005.

12 Fewer Relapses in Liver and Lymph Nodes with Capecitabine Number of relapses Capecitabine n = 1,004 Bolus 5-FU/LV n = 983 Total As only siteTotal As only site Total number of relapses323357 Colon, rectum58416043 Lymph nodes44205735 Liver12693145110 Lung58355839 Other101689965

13 * Data points from KM curves Sources: 1 Haller DG et al. J Clin Oncol 2004; In Press 2 André T et al. J Clin Oncol 2003;15:2896–903 3 IMPACT. Lancet 1995;345(8955):939–44 X-ACT Mayo Comparable to Mayo in Other Trials (Dukes’ C, Colon Only) INT0089* n = 769 1 Andre* n = 256 2 IMPACT n = 313 3 X-ACT n = 983 Mayo 3-year DFS 63616261 Mayo 3-year OS 738178

14 Treatment Exposure Median dose intensity  Capecitabine 93% (quartiles 77-100%)  Bolus 5-FU/LV 92% (quartiles 78-100%) Patients completing >12 weeks treatment at full dose  Capecitabine 75%  Bolus 5-FU/LV 67% Majority of patients completed the full course of treatment  Capecitabine 84% completed all 8 cycles  Bolus 5-FU/LV 89% completed all 6 cycles

15 Fewer Key Grade III/IV Toxicities and Later Onset with Capecitabine 1.0 0.8 0.6 0.4 0.2 0 p < 0.001 012345678012345678 Months 5-FU/LV Capecitabine Overall safety profile: Grade III to IV diarrhea, stomatitis, nausea, vomiting, alopecia, HFS, neutropenia Source: Cassidy J. Presentation. ASCO 2005. Estimated probability of Grade III/IV adverse event

16 * p < 0.001 † Laboratory value Treatment-related AEs * * * * Diarrhea Stomatitis Hand-foot Neutropenia † Nausea/ Alopecia syndromevomiting 100 80 60 40 20 0 Capecitabine (n = 993) Bolus 5-FU/LV (n = 974) * * Patients (%) Toxicity

17 Number of cycles Before AfterBeforeAfterBeforeAfter Hand-foot syndrome Diarrhea Stomatitis Grade II Grade III Grade IV 20 15 10 5 0 Capecitabine Dose Modification Reduces the Recurrence of Adverse Events

18 Improved Tolerability Profile of Capecitabine Maintained in Elderly All grades Capecitabine (%)Bolus 5-FU/LV (%) ≥70 years (n = 186) ≥70 years (n = 205) Diarrhea5268 Stomatitis2367 Hand-foot syndrome638 Nausea3347 Fatigue1719 Neutropenia431

19 1.0 0.8 0.6 0.4 0.2 0 Estimated probability 0122436486072 Months Full dose capecitabine Inter dose capecitabine Low dose capecitabine Capecitabine Efficacy Maintained with Appropriate Dose Reduction: DFS 5325104594033322801941136112400 343323293265218174122813713500 12090777060503420103100 No. at risk Full dose Inter dose Low dose

20 X-ACT: Quality of Life Maintained Over Time (QLQ C-30) 5-FU / LV Capecitabine 100 80 60 40 20 0 Baseline79161725 Weeks (of trial treatment) 889817894912 841746838865 n = Global health status score Source: Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.

21 *Also balanced first- versus second-line chemotherapy Poststudy Chemotherapy after Relapse Similar in Both Arms Percent patients with chemotherapy* Capecitabine n = 372 5-FU/LV n = 404 Regimens based on: 5-FU1716 Irinotecan3935 Oxaliplatin3229 Capecitabine410 Others96

22 -1864 1450 -3004 -57 -259 7 Net costs per patient versus 5-FU/LV (£) 4 000 2 000 0 –2 000 –4 000 Total Drugs Administration Hospital Medications Consultations use Sources: Updated from Douillard J-Y et al. Ann Oncol 2004;15(Suppl 3):iii73; Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005. Replacement of 5-FU/LV with Xeloda is Net Cost Saving: Direct Payer Costs

23 X-ACT Trial Conclusions Disease-free survival for capecitabine at least equivalent to 5-FU/leucovorin Capecitabine improved relapse-free survival Capecitabine associated with significantly fewer adverse events Capecitabine is an effective alternative to IV 5-FU/leucovorin as adjuvant therapy in patients with Stage III disease


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