Capecitabine versus bolus 5 fu leucovorin as adjuvant therapy for colon cancer x act trial results
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James Cassidy, MD Colorectal Cancer Update Think Tank Meeting June 24, 2005 PowerPoint PPT Presentation


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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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James Cassidy, MD Colorectal Cancer Update Think Tank Meeting June 24, 2005

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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

0123456

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

0123456

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

0123456

Years

Source: Cassidy J. Presentation. ASCO 2005.


Fewer relapses in liver and lymph nodes with capecitabine

Fewer Relapses in Liver and Lymph Nodes with Capecitabine


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

  • 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 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

012345678

Months

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

Source: Cassidy J. Presentation. ASCO 2005.


Toxicity

Toxicity

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 syndromevomiting

* 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 AfterBeforeAfterBeforeAfter

Hand-foot syndrome Diarrhea Stomatitis


Improved tolerability profile of capecitabine maintained in elderly

Improved Tolerability Profile of CapecitabineMaintained in Elderly


Capecitabine efficacy maintained with appropriate dose reduction dfs

Capecitabine Efficacy Maintained with Appropriate Dose Reduction: DFS

1.0

0.8

0.6

0.4

0.2

0

Estimated probability

Full dose capecitabine

Inter dose capecitabine

Low dose capecitabine

0122436486072

Months

No. at riskFull dose

Inter dose

Low dose

5325104594033322801941136112400

343323293265218174122813713500

12090777060503420103100


X act quality of life maintained over time qlq c 30

X-ACT: Quality of Life Maintained Over Time (QLQ C-30)

100

80

60

40

20

0

Global health status score

5-FU/LV

Capecitabine

Baseline79161725

Weeks (of trial treatment)

n =

n =

889817894912

841746838865

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


Poststudy chemotherapy after relapse similar in both arms

Poststudy Chemotherapy after RelapseSimilar in Both Arms

*Also balanced first- versus second-line chemotherapy


James cassidy md colorectal cancer update think tank meeting june 24 2005

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

  • 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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