What is the role of capecitabine (Xeloda) in the Create-X trial?

Role of Capecitabine in the CREATE-X Trial

Capecitabine significantly improved disease-free survival and overall survival in patients with HER2-negative breast cancer who had residual invasive disease after standard preoperative anthracycline- and taxane-based chemotherapy in the CREATE-X trial. 1

Trial Design and Patient Population

• The CREATE-X (Capecitabine for Residual Cancer as Adjuvant Therapy) was a phase III randomized clinical trial that enrolled 910 Asian patients with stages I to IIIB, HER2-negative breast cancer 1
• Eligible patients had centrally confirmed residual invasive disease at surgery in the breast and/or axillary nodes following standard preoperative anthracycline, taxane, or combined anthracycline and taxane therapy 1
• The trial included patients with both hormone receptor-positive (68%) and hormone receptor-negative (32%) disease, with 57% of patients being premenopausal at study entry 1

Capecitabine Dosing and Administration

• Patients in the capecitabine arm received six to eight cycles of oral capecitabine at a dosage of 1,250 mg/m² orally twice daily on days 1 through 14 of a 21-day cycle 1
• This dosage was found to be excessively toxic in non-Asian patients aged 65 and older, leading to protocol amendments in other studies to reduce the starting dose to 1,000 mg/m² twice daily without dose escalation 1

Efficacy Outcomes

• The trial was terminated early after the primary endpoint of disease-free survival (DFS) was met 1
• After a median follow-up of 3.6 years, the 5-year DFS rate was 74.1% in the capecitabine arm versus 67.6% in the control arm (HR 0.70; 95% CI, 0.53-0.92; p=0.01), representing an absolute difference of 6.5% 1
• Overall survival (OS), a secondary endpoint, was also significantly improved in the capecitabine group: 89.2% versus 83.6% (HR 0.59; 95% CI, 0.39-0.90; p=0.01), with an absolute difference of 5.6% 1

Subgroup Analysis by Hormone Receptor Status

• Patients with triple-negative breast cancer showed greater benefit: DFS (69.8% vs 56.1%, HR 0.58,95% CI 0.39-0.87) and OS (78.8% vs 70.3%, HR 0.52,95% CI 0.30-0.90) 1
• Hormone receptor-positive patients also derived benefit, though numerically smaller: DFS (76.4% vs 73.5%, HR 0.81,95% CI 0.55-1.17) and OS (93.4% vs 90%, HR 0.73,95% CI 0.38-1.40) 1
• The interaction test for treatment effect by hormone receptor status was not statistically significant (p=0.21), suggesting benefit across subgroups 1
• Recent reviews found that adjuvant capecitabine improved OS by a relative reduction of 12%-30% in patients with TNBC but little evidence of impact in those with HR-positive disease 1

Safety and Tolerability

• Hand-foot syndrome was the most frequent adverse event, occurring in 73.4% of patients in the capecitabine group, with 11.1% experiencing grade 3 events 1, 2
• Other common adverse events included neutropenia (6.3%), diarrhea (2.9%), and hand-foot syndrome (11.1%) 1
• Toxicity concerns are particularly important in older patients; in the CALGB 49907 trial, patients ≥65 years had a 34% rate of grade 3 or higher toxicity, including two protocol-related deaths, leading to dose reduction recommendations 1, 2

Clinical Implementation

• Based on CREATE-X results, ASCO guidelines recommend that patients with early-stage, HER2-negative breast cancer with pathologic invasive residual disease after standard preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine 1
• The expert panel preferentially supports the use of adjuvant capecitabine in patients with hormone receptor-negative, HER2-negative breast cancer, though benefit cannot be excluded in hormone receptor-positive patients 1
• The findings from CREATE-X are being extended in the ongoing phase III EA1131 trial of adjuvant capecitabine versus platinum chemotherapy for patients with triple-negative breast cancer with residual invasive disease 1

Important Considerations and Caveats

• Despite the convenience of oral administration, capecitabine can be associated with life-threatening toxicity, requiring careful patient selection and monitoring 1
• Dose adjustments are necessary for patients with renal insufficiency since elimination is primarily renal 2
• The CREATE-X trial was conducted primarily in Asian patients, and toxicity profiles may differ in other populations 1, 3
• Patients with partial or complete DPD deficiency (3-5% of population) may experience potentially life-threatening toxicity 2