Adding Capecitabine to Systemic Therapies Improves Outcomes in Triple-Negative Breast Cancer

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Capecitabine improves disease-free and overall survival for patients with triple-negative breast cancer, but only when it is added to other systemic therapies, not when it is used as a substitute, according to a large meta-analysis of the effects of capecitabine in early breast cancer, The results of the meta-analysis were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) by Marion van Mackelenbergh, MD, of the University of Kiel, Germany.1

Marion van Mackelenbergh, MD

Marion van Mackelenbergh, MD

“Capecitabine did not alter overall disease-free survival, but when added to other systemic therapies, there was an improvement. Overall survival was also improved when capecitabine was given in addition to other therapies. There is no evidence supporting a predictive value of capecitabine-specific adverse events on outcome. It can be concluded that the addition of capecitabine to other treatment may be recommended for patients with triple-negative breast cancer,” Dr. van Mackelenbergh stated.

Dr. Mackelenbergh said there was one caveat: “The meta-analysis showed no data comparing the effects of capecitabine with carboplatin in triple-negative breast cancer. One trial is recruiting patients to evaluate this in the post-neoadjuvant setting. The effect of capecitabine compared with other systemic therapies, including carboplatin, remains to be investigated.”

Capecitabine is approved by the U.S. Food and Drug Administration (FDA) for use as monotherapy or in combination with docetaxel in metastatic breast cancer. The -meta-analysis results addressed its use in early breast cancer.

Several randomized trials have evaluated the effect of capecitabine in early breast cancer, mainly in high-risk patients. The German Breast Group investigators sought to examine the effect of capecitabine in patients with early breast cancer on disease-free survival as the primary objective; secondary endpoints included the effect of capecitabine on overall survival and to determine whether there was an interaction between capecitabine-specific toxicity and treatment effect.

“Capecitabine did not alter overall disease-free survival, but when added to other systemic therapies, there was an improvement.”
— Marion van Mackelenbergh, MD

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Study Details

The meta-analysis included individual patient data from 15,457 patients enrolled in 12 randomized controlled trials; 7,983 patients with early breast cancer were treated with capecitabine, and 7,474 patients were in the control arms. Five of the trials included in the meta-analysis addressed capecitabine given instead of other therapies, and seven evaluated the use of capecitabine in addition to other therapies. The analysis was performed on the overall study population and in two predefined subsets: patients who received capecitabine in addition to other therapies and those who received capecitabine instead of another systemic treatment.

The median age of patients at initial diagnosis was 53 years. Nearly three-quarters of patients had nodal involvement; 56% presented with tumor stage II disease; about 68% had hormone receptor–positive disease; 45% had high-grade disease; 15% had HER2-positive breast cancer. About 80% of the patients were treated in the adjuvant setting and almost 20%, in the neoadjuvant setting.

Key Outcomes

Among the entire data set, there was no significant effect of capecitabine on disease-free survival, but a significant benefit was observed in the patients who received capecitabine in addition to other systemic therapies (hazard ratio [HR] = 0.888, 95% confidence interval [CI] = 0.817–0.965). “Only the CREATE-X trial had positive results for disease-free survival, and no benefit of capecitabine on disease-free survival was observed when capecitabine was given instead of another treatment,” noted Dr. Mackelenbergh.

A slight benefit for capecitabine was observed in overall survival for the total data set (HR = 0.892, 95% CI = 0.824–0.965; P = .005), which was more pronounced when capecitabine was added to other systemic therapies (HR = 0.837, 95% CI = 0.751–0.933; P = .001). “Only the CREATE-X and USON 01062 trials were positive for overall survival. There was no overall survival benefit [in the meta-analysis] when capecitabine was substituted for another systemic therapy,” she emphasized.

In patients with triple-negative breast cancer, capecitabine improved disease-free survival by 18% when added to standard chemotherapy and overall survival by 22% (P = .004 for both analyses). Dr. Mackelenbergh emphasized that “the only benefit of capecitabine was observed in the triple-negative breast cancer overall cohort and when capecitabine was added [to another therapy].” No benefit was observed in triple-negative breast cancer when capecitabine was given instead of another systemic therapy.

The most common grade 3 and 4 toxicities associated with capecitabine were mucositis, hand-foot syndrome, and diarrhea. No significant associations were reported between capecitabine-specific toxicities and treatment benefit.

Additional Comments

“It remains to be seen whether capecitabine or carboplatin is more effective in triple-negative breast cancer.”
— Steven J. Isakoff, MD, PhD

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“Since the publication of the CREATE-X results, capecitabine has been a reasonable option for triple-negative breast cancer. The meta-analysis results support this,” said ­Steven J. Isakoff, MD, PhD, a medical oncologist at Massachusetts General Hospital Cancer Center, Boston. “There is no benefit in the estrogen receptor–positive patients, and the benefit is limited to the triple-negative breast cancer population.

“The studies included in the meta-analysis were a mix. The findings confirm a signal we have seen in a larger population, demonstrating more robustly not to substitute capecitabine for other therapies, but it could be added to patients with triple-negative breast cancer who are at higher risk of recurrence,” continued Dr. Isakoff.

“It remains to be seen whether capecitabine or carboplatin is more effective in triple-negative breast cancer. The phase III ECOG 1131 trial will compare carboplatin vs capecitabine in patients with residual disease in the postoperative setting. Toxicity will be an issue, too,” Dr. Isakoff said. “We await these results.” 

DISCLOSURE: Dr. van Mackelenbergh reported relationships with AstraZeneca, Amgen, Novartis, and Lilly. Dr. Isakoff has served as a consultant or advisor to AbbVie, Genentech/Roche, Hengrui Therapeutics, Immunomedics, Myriad Genetics, and Puma Biotechnology; and has received institutional research funding from AbbVie, AstraZeneca/MedImmune, Genentech, Merck, OncoPep, and PharmaMar.


1. van Mackelenbergh M, Seither F, Möbus V, et al: Effects of capecitabine as part of neo-/adjuvant chemotherapy: A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-07. Presented December 11, 2019.