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Low-Dose Capecitabine Maintenance Therapy Improves Survival in Patients with Triple-Negative Breast Cancer

JHOP - April 2021 Vol 11, No 2 - From the Literature, Breast Cancer, Dose Escalation/Reduction
With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus, University of California, San Francisco; Professor Emeritus, Touro University–California, Mare Island, Vallejo, CA
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BACKGROUND: Patients with triple-negative breast cancer (TNBC) have a high relapse rate and poor outcomes after standard treatment. Capecitabine is a chemotherapy that is used widely in the treatment of metastatic breast cancer. In a recent study (SYSUCC-001), researchers evaluated the efficacy and safety of low-dose capecitabine maintenance after standard adjuvant chemotherapy in patients with early-stage TNBC.

METHODS: SYSUCC-001 was an open-label, multicenter, randomized, phase 3 study in China that included 443 patients with early-stage TNBC who had completed standard adjuvant chemotherapy. The patients were randomized in a 1:1 ratio to low-dose (650 mg/m2 twice daily) capecitabine continuously for 1 year (N = 222) or to an observational group (N = 221). The primary end point was 5-year disease-free survival (DFS). The secondary end points included distant DFS, overall survival (OS), locoregional recurrence-free survival, and adverse events.

RESULTS: Of the 443 patients who were randomized, 434 completed the trial. With a median follow-up of 61 months, 94 events were observed, including 38 events (37 disease recurrences and 32 deaths) in the capecitabine arm and 56 events (56 recurrences and 40 deaths) in the observation arm. The estimated 5-year DFS was significantly improved in the capecitabine group compared with the observation group (82.8% vs 73%, respectively; hazard ratio [HR] for risk of recurrence or death, 0.64; 95% confidence interval [CI], 0.42-0.95; P = .03). The estimated 5-year distant DFS rate was 85.8% and 75.8%, respectively (HR, 0.6; 95% CI, 0.38-0.92; P = .02). The treatment effects on DFS were consistent across all subgroups; however, capecitabine was not associated with significant improvement in the estimated 5-year OS or the estimated 5-year locoregional recurrence-free survival versus the observation group (85.5% vs 85% and 81.3% vs 80.8%, respectively). Low-dose capecitabine was generally well-tolerated. The most common capecitabine-related adverse event was hand-foot syndrome in 100 patients (45.2%), of which 7.7% were grade 3. Other common grade 1 or 2 adverse events in the capecitabine group included leukopenia (23.5%), elevated bilirubin (12.7%), abdominal pain or diarrhea (6.8%), and elevated alanine aminotransferase or aspartate transaminase levels (5%). “The current trial demonstrated that a year of capecitabine was tolerable for most women without significant treatment discontinuation due to toxicity,” stated the researchers.

Source: Wang X, Wang SS, Huang H, et al. Effect of capecitabine maintenance therapy using lower dosage and higher frequency vs observation on disease-free survival among patients with early-stage triple-negative breast cancer who had received standard treatment: the SYSUCC-001 randomized clinical trial. JAMA. 2021;325:50-58.

Commentary by Robert J. Ignoffo

The SYSUCC-001 study has been eagerly anticipated for clarifying the role of capecitabine in early triple-negative breast cancer. The reported study outlined the statistical considerations required for adequate analysis. To detect an absolute improvement of 12% in the 5-year disease-free survival from 68% in the control group to 80% in the capecitabine maintenance group, approximately 109 DFS events would be required to achieve 80% power at a 2-sided significance level of 5%. However, this study did not reach the required number of events to satisfy the statistical analysis (ie, 94 vs 109 events). The study investigators followed the independent data monitoring committee’s advice and performed the final analysis with 3 years of follow-up and 94 events, rather than the projected 109 events.

Capecitabine was administered in an uninterrupted lower-dose schedule, so-called a metronomic design. The metronomic regimen caused less reports of fatigue, low blood counts, mucositis, diarrhea, and hand-foot syndrome than the traditional capecitabine dosing, making the regimen well-tolerated by cancer chemotherapy standards. Patients in this study received approximately 50% of the usual daily dose of capecitabine (approximately 1000 mg twice daily), every day, for 1 year. The usual dose schedules of capecitabine have consisted of a higher drug dose, for 14 consecutive days, followed by a 7-day break for 6 or more cycles.

The results of the SYSUCC-001 study did indeed show a benefit in DFS and in distant disease–free survival, but not in OS or in locoregional recurrence-free survival. The authors stated that these results were consistent with the Masuda study,1 which showed that capecitabine was safe and significantly effective in prolonging DFS and OS among patients with HER2-negative breast cancer who had residual invasive disease. However, 69% of the study group had estrogen receptor–positive disease. Therefore, it is uncertain if this is a valid comparison.

The SYSUCC-001 study was very well-designed, with excellent statistical analysis. The results of this study should be added to the treatment options for postadjuvant management of patients with TNBC.

  1. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376:2147-2159.
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