Capecitabine versus bolus 5 fu leucovorin as adjuvant therapy for colon cancer x act trial results
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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 Meeting June 24, 2005. X-ACT Trial in Adjuvant Treatment of Dukes’ C Colon Cancer. Capecitabine

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Capecitabine versus bolus 5 fu leucovorin as adjuvant therapy for colon cancer x act trial results

Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for Colon Cancer: X-ACT Trial Results

James Cassidy, MDColorectal Cancer Update Think Tank MeetingJune 24, 2005


X act trial in adjuvant treatment of dukes c colon cancer
X-ACT Trial in Adjuvant Treatment of Dukes’ C Colon Cancer

Capecitabine

1,250 mg/m2 twice daily, d1–14, q21d

n = 1,004

Recruitment

1998–2001

  • 1° endpoint: Disease-free survival (DFS)

  • 2° endpoints

    • Relapse-free survival (RFS)

    • Overall survival

    • Tolerability (NCIC CTC)

    • Pharmacoeconomics

    • QoL

Chemo-naïve

Dukes’ C,

resection ≤8 weeks

Bolus 5-FU/LV

5-FU 425 mg/m2 plus LV 20 mg/m2, d1–5, q28d

n = 983

Source: Cassidy J. Presentation. ASCO 2005.


X act powered to establish at least equivalence of capecitabine
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.


Standard eligibility criteria
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.


Protocol defined populations and endpoints
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.


X act treatment schedules
X-ACT Treatment Schedules

Capecitabine1,250 mg/m2 twice daily

Rest (days 15–21)

Treatment (days 1–14)

Repeat cycle x 8

(24 weeks)

OR

Day

Bolus 5-FU/LV

IV leucovorin20 mg/m2 +

IV 5-FU 425 mg/m2

1 2 3 4 5

8

15

21

28

Repeat cycle x 6

(24 weeks)

Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.


X act treatment arms were well balanced
X-ACT Treatment Arms Were Well Balanced

Source: Cassidy J. Presentation. ASCO 2005.


Other prognostic factors were balanced
Other Prognostic Factors Were Balanced

Source: Twelves C. Presentation. ASCO 2005.


Strong trend to superior dfs itt
Strong Trend to Superior DFS (ITT)

1.0

0.8

0.6

0.4

Capecitabine (n = 1,004) 64.6%

5-FU/LV (n = 983) 61%

HR = 0.87 (95% CI: 0.75–1.00)p < 0.0001

Estimated probability

0 1 2 3 4 5 6

Years

Median follow-up 51 months

Source: Twelves C. Presentation. ASCO 2005.


Capecitabine versus bolus 5 fu lv superior relapse free survival itt
Capecitabine versus Bolus 5-FU/LV: Superior Relapse-Free Survival (ITT)

1.0

0.8

0.6

0.4

Capecitabine (n = 1,004)

5-FU/LV (n = 983)

HR = 0.86 (95% CI: 0.74–0.99)p = 0.0407

Estimated probability

0 1 2 3 4 5 6

Years

Source: Cassidy J. Presentation. Colorectal Cancer UpdateThink Tank Meeting 2005.


Capecitabine showed trend to improved overall survival itt
Capecitabine Showed Trend to Improved Overall Survival (ITT)

Capecitabine (n = 1,004) 81.7%

5-FU/LV (n = 983) 78.3%

1.0

0.8

0.6

0.4

Estimated probability

HR = 0.89 (95% CI: 0.74–1.07)p < 0.001

0 1 2 3 4 5 6

Years

Source: Cassidy J. Presentation. ASCO 2005.



X act mayo comparable to mayo in other trials dukes c colon only
X-ACT Mayo Comparable to Mayo in Other Trials (Dukes’ C, Colon Only)

* Data points from KM curves

Sources: 1 Haller DG et al. J Clin Oncol 2004; In Press2 André T et al. J Clin Oncol 2003;15:2896–9033 IMPACT. Lancet 1995;345(8955):939–44


Treatment exposure
Treatment Exposure Colon Only)

  • 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


Fewer key grade iii iv toxicities and later onset with capecitabine
Fewer Key Grade III/IV Toxicities and Colon Only)Later Onset with Capecitabine

1.0

0.8

0.6

0.4

0.2

0

5-FU/LV

Capecitabine

p < 0.001

Estimated probability of Grade III/IV adverse event

0 1 2 3 4 5 6 7 8

Months

Overall safety profile: Grade III to IV diarrhea, stomatitis, nausea, vomiting, alopecia, HFS, neutropenia

Source: Cassidy J. Presentation. ASCO 2005.


Toxicity
Toxicity Colon Only)

Treatment-related AEs

100

80

60

40

20

0

Capecitabine (n = 993)

Bolus 5-FU/LV (n = 974)

Patients (%)

*

*

*

*

*

*

Diarrhea Stomatitis Hand-foot Neutropenia† Nausea/ Alopecia syndrome vomiting

* p < 0.001

† Laboratory value


Capecitabine dose modification reduces the recurrence of adverse events
Capecitabine Dose Modification Reduces the Recurrence of Adverse Events

20

Grade II

Grade III

Grade IV

15

Number of cycles

10

5

0

Before After Before After Before After

Hand-foot syndrome Diarrhea Stomatitis


Improved tolerability profile of capecitabine maintained in elderly
Improved Tolerability Profile of Adverse EventsCapecitabineMaintained in Elderly


Capecitabine efficacy maintained with appropriate dose reduction dfs
Capecitabine Efficacy Maintained with Appropriate Adverse EventsDose Reduction: DFS

1.0

0.8

0.6

0.4

0.2

0

Estimated probability

Full dose capecitabine

Inter dose capecitabine

Low dose capecitabine

0 12 24 36 48 60 72

Months

No. at riskFull dose

Inter dose

Low dose

532 510 459 403 332 280 194 113 61 12 4 0 0

343 323 293 265 218 174 122 81 37 13 5 0 0

120 90 77 70 60 50 34 20 10 3 1 0 0


X act quality of life maintained over time qlq c 30
X-ACT: Quality of Life Maintained Over Time Adverse Events(QLQ C-30)

100

80

60

40

20

0

Global health status score

5-FU/LV

Capecitabine

Baseline 7 9 16 17 25

Weeks (of trial treatment)

n =

n =

889 817 894 912

841 746 838 865

Source: Cassidy J. Presentation. Colorectal Cancer UpdateThink Tank Meeting 2005.


Poststudy chemotherapy after relapse similar in both arms
Poststudy Chemotherapy after Relapse Adverse EventsSimilar in Both Arms

*Also balanced first- versus second-line chemotherapy


Replacement of 5-FU/LV with Xeloda is Net Cost Saving: Direct Payer Costs

Net costs per patient versus 5-FU/LV (£)

4000

2000

0

–2000

–4000

1450

7

-57

-259

-1864

-3004

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.


X act trial conclusions
X-ACT Trial Conclusions Direct Payer Costs

  • 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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