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Adjuvant capecitabine prolongs survival in HER-2–negative breast cancer with residual disease
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The addition of adjuvant capecitabine to standard postsurgical treatment safely prolonged DFS and OS in women with HER-2–negative breast cancer who had residual invasive carcinoma after neoadjuvant chemotherapy, according to results of the CREATE-X trial published in The New England Journal of Medicine.
Patients with residual invasive breast cancer after receiving neoadjuvant chemotherapy — which usually contains an anthracycline, taxane or both — are at high risk for relapse, and no adjuvant chemotherapy has been established for these patients.
Capecitabine has shown promise for the adjuvant treatment of gastrointestinal cancer and is often used as second-line therapy for patients with breast cancer resistant to anthracycline, taxane or both.
Masakazu Toi, MD, PhD, professor of breast surgery at Kyoto University Hospital in Japan, and colleagues evaluated data from 910 patients (median age, 48 years; range, 25-74) from Japan and South Korea randomly assigned 1:1 to receive standard postsurgical treatment alone or with capecitabine. Nearly 40% of patients had stage IIIa or IIIb breast cancer, and 32.2% had triple-negative disease.
After the interim safely analysis, researchers extended capecitabine treatment from six cycles to eight cycles. Thus, 159 patients received six cycles — 57.9% of whom completed treatment at the planned dose — and 283 received eight cycles, 37.8% of whom completed treatment.
DFS served as a primary endpoint, and OS served as a secondary endpoint.
Median follow-up was 3.6 years.
A greater proportion of patients in the capecitabine group achieved 5-year DFS (74.1% vs. 67.6%; HR for recurrence, second cancer or death = 0.7; 95% CI, 0.53-0.92) and 5-year OS (89.2% vs. 83.6%; HR for death = 0.59; 95% CI, 0.39-0.9).
The benefit with capecitabine persisted for patients with triple-negative disease in terms of 5-year DFS (69.8% vs. 56.1%; HR = 0.58; 95% CI, 0.39-0.87) and 5-year OS (78.8% vs. 70.3%; HR = 0.52; 95% CI, 0.3-0.9).
Because the prespecified interim efficacy analysis showed the study reached the primary endpoint, researchers ended the trial early.
Hand–foot syndrome occurred in 325 patients (73.4%) treated with capecitabine, 49 of whom (11.1%) had a grade 3 or worse event.
The most frequent hematologic adverse events in the capecitabine arm included leukopenia, thrombocytopenia, neutropenia and anemia. The most frequent nonhematologic events included fatigue; nausea; diarrhea; stomatitis; and increases in alanine aminotransferase, bilirubin, lactate dehydrogenase, aspartate aminotransferase and alkaline phosphate levels.
In total, 6.3% of patients in the capecitabine experienced a grade 3 or grade 4 adverse event.
Two aspects of the study may account for the positive outcomes, Toi and colleagues wrote.
“First, the trial targeted a population of patients who did not have a pathological complete response, a group whose survival outcomes are known to be unfavorable,” they wrote. “... We excluded patients who had a pathological complete response, who were likely to be cured with standard chemotherapy regimens. Therefore, this exclusion enriched the trial population for patients who may benefit from additional therapy.
“Second, this trial used an effective schedule of the fluorouracil-based antimetabolite; capecitabine therapy was compared with no chemotherapy as postoperative adjuvant therapy,” they added. “In fact, 60% of the patients in our trial had residual invasive cancer after receiving an IV bolus infusion of fluorouracil as a component of neoadjuvant chemotherapy. ... Anthracyclines and taxanes are able to induce thymidine phosphorylase, an enzyme that activates capecitabine.” – by Alexandra Todak
Disclosure: Toi reports grants from Chugai Pharmaceutical outside the study. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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