Adjuvant Capecitabine Boosts Survival Rates in HER2-Negative Breast Cancer

A combination of capecitabine and adjuvant therapy dropped the risk of recurrence by 30% and prolonged survival by 40% for patients with residual breast cancer post-neoadjuvant chemotherapy and surgery, according to phase III data.

Masakazu Toi, MD, PhD

A combination of capecitabine and adjuvant therapy dropped the risk of recurrence by 30% and prolonged survival by 40% for patients with residual breast cancer post-neoadjuvant chemotherapy and surgery, according to phase III data presented at the 2015 San Antonio Breast Cancer Symposium (SABCS).

After 5 years of follow-up, the disease-free survival (DFS) rate with capecitabine was 74.1%, versus 67.6% with standard therapy alone (HR, 0.70;P= .00524). The 5-year overall survival (OS) rate with capecitabine was 89.2%, versus 83.9% in the standard therapy arm (HR, 0.60;P<.01).

“After standard neoadjuvant chemotherapy containing an anthracycline and/or taxane, postoperative adjuvant use of capecitabine improved disease-free survival,” said lead investigator Masakazu Toi, MD, PhD, professor, Kyoto University Hospital in Japan, founder and senior director of the Japan Breast Cancer Research Group. “Overall survival was significantly improved by capecitabine adjuvant therapy for non-pCR or node-positive patients after neoadjuvant chemotherapy.”

In the phase III study, 910 patients were enrolled, with 885 going on to receive capecitabine (n = 440) or standard therapy (n = 445). All patients were non-pathologic complete responders and/or had positive lymph nodes following surgery and neoadjuvant treatment with an anthracycline and/or taxane for HER2-negative breast cancer. The primary endpoint of the study was DFS. Secondary outcome measures focused on OS and safety.

Standard therapy included radiation and hormonal therapy, when applicable for patients with HR-positive disease. Oral capecitabine was administered for 8 cycles at 1250 mg/m2 twice daily for 2 weeks followed by 1 week without treatment. The study was originally designed to treat patients for 6 cycles; however, following an interim safety analysis, this was extended to 8 cycles.

Adjuvant endocrine therapy was utilized in the capecitabine arm for 42.5% and 24.5% of pre- and post-menopausal patients, respectively. In the control arm, the rates of adjuvant endocrine therapy use were 40% and 28.5%, for pre- and post-menopausal patients. Hormonal therapy was primarily delivered concurrently with capecitabine. Radiation therapy was received by 72.3% of patients in the capecitabine arm and for 73.5% of those in the control arm.

The median age of patients in the study was 48 years. All patients were enrolled in Korea (n = 304) and Japan (n = 606). Overall, nearly two-thirds of patients were HR-positive (63.5%). In the capecitabine arm, 58.9% of patients had stage I/IIA/IIB disease and 40.5% had stage IIIA/IIIB breast cancer. In the control arm, 62% of patients had stage I/IIA/IIB disease and 37.5% had stage IIIA/IIIB cancer.

The 3-year DFS rate was 82.8% with capecitabine compared with 74.0% in the standard therapy arm. The 3-year OS rate was 94% versus 89.2%. Early findings were not yet statistically significant for OS but passed the bar for significance at the 5-year analysis, said Toi.

Across all treatment groups, capecitabine was superior to standard therapy alone for DFS. For those with ypN1 after neoadjuvant therapy and surgery (n = 339), there was a 46% reduction in the risk of recurrence with capecitabine (HR, 0.54). However, in patients with ypN0 (n = 345) and for those with ypN2/3 (n = 199), the benefits were less pronounced with capecitabine, with hazard ratios of 0.88 and 0.82, respectively.

Those with HR-negative disease (n = 296) experienced a 42% reduction in the risk of recurrence with capecitabine (HR, 0.58). In the HR-positive group (n = 561), the benefit with capecitabine was less pronounced (HR, 0.84). Subgroup analyses are ongoing to assess the impact of capecitabine in patients with triple-negative breast cancer, said Toi.

“The balance of benefit and toxicity would favor the use of capecitabine in the post-neoadjuvant chemotherapy situation, but prediction for the therapeutic benefit needs to be investigated further,” he said.

Across all patients in the study, 58% of the 159 who planned to receive 6 cycles of capecitabine completed therapy. In this group, there were dose reductions for 38 patients and 18.2% of patients discontinued therapy, for a relative dose intensity of 21.6%. In the 8-cycle arm, 37.9% of 280 patients completed therapy. Overall, 37.1% and 25% of patients underwent a dose reduction or discontinued treatment, respectively. The relative dose intensity was 29%.

The most common grade 3 adverse event associated with capecitabine was hand-foot syndrome (10.9%). There were no grade 4 events and the overall incidence of hand-foot syndrome was 72.3%.

There was a significantly higher rate of neutropenia in the capecitabine arm versus the control (6.6% vs 1.6%;P<.001). Additionally, diarrhea was significantly more common with capecitabine versus the control (3% vs 0.4%;P= .004).

“The dose of capecitabine, even though toxic, was better tolerated than we would expect in the United States, where we treat patients routinely with 2000 mg/m2,” commented Hope S. Rugo, MD, director, Breast Oncology Clinical Trials Program, University of California, San Francisco, during a discussion at SABCS. “In the Japanese population, we have seen that patients can tolerate a higher dose. There could be a pharmacogenomic effect.”

The study was designed to follow patients for 5 years. At this follow-up, based on the benefit seen with the addition of capecitabine to standard adjuvant therapy, an independent data monitoring committee recommended the discontinuation of the study.

Subset analyses exploring the impact of hormonal therapy on outcomes are currently being conducted for overall survival. Additionally, cost-effectiveness and subgroup analyses are under way, including those looking at the differences in outcomes between the two doses, explained Toi.


  1. Lee S-J, Toi M, Ohtani S, et al. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X/JBCRG-04). Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract: S1-07.