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Adjuvant capecitabine extends DFS among women with HER-2–negative, residual invasive disease
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SAN ANTONIO — Adjuvant capecitabine prolonged DFS among women with HER-2–negative breast cancer who had pathologic residual invasive disease following neoadjuvant chemotherapy containing an anthracycline and/or taxane, according to open-label, phase 3 study results presented at the San Antonio Breast Cancer Symposium.
“Patients with pathologic residual invasive disease after neoadjuvant chemotherapy have higher risk for relapse,” Masakuza Toi, MD, PhD, professor at Kyoto University Hospital in Japan, as well as founder and senior director of the Japan Breast Cancer Research Group, said during a press conference. “It is unclear whether postoperative systemic chemotherapy following neoadjuvant chemotherapy is able to prolong survival.”
Masakuza Toi
To answer this question, Toi and colleagues conducted a multicenter trial to evaluate the efficacy of adjuvant capecitabine among women with residual invasive disease, defined as non-pathological complete response or node-positive disease following neoadjuvant chemotherapy with an anthracycline and/or taxane.
DFS served as the study’s primary endpoint. Secondary endpoints included OS, safety and cost-effectiveness.
Researchers enrolled 910 patients from Korea (n = 304) and Japan (n = 606). The full analysis set included 445 patients randomly assigned to the control arm — or radiation therapy and hormone therapy as appropriate — and 440 patients assigned capecitabine (2,500 mg/m2 daily days 1-14 every 3 weeks). Although the trial started with 6 cycles of capecitabine, a safety analysis conducted in 2013 indicated 8 cycles of capecitabine was feasible.
Median age in both arms was 48 years, and 63.5% of the cohort was hormone receptor positive.
Among patients in the capecitabine arm, 200 received hormone therapy concurrently with chemotherapy, and 24 received it after. The relative dose intensity of capecitabine was 78.8%.
In 2015, researchers conducted the first preplanned interim analysis after 2 years of follow-up, after which the study was stopped based on the study protocol and a recommendation from the independent data monitoring committee.
Overall, significantly more women in the capecitabine arm vs. control arm achieved 3-year DFS (82.8% vs. 74%) and 5-year DFS (74.1% vs. 67.7%; HR = 0.7; 95% CI, 0.53-0.93).
At the time of the interim analysis, there were 28 OS events in the capecitabine arm vs. 41 in the control arm. More women in the capecitabine arm achieved 2-year OS (96.2% vs. 93.9%), which indicated a trend toward improved OS with capecitabine (HR = 0.65; 95% CI, 0.4-1.06).
However, after an analysis conducted with additional follow-up in Sept. 2015, the difference in OS was statistically significant, but the data were not available at the time of the presentation, Toi said.
Data from the interim analysis showed grade 3 and grade 4 toxicities that occurred in the capecitabine arm included hand–foot syndrome (11%), neutropenia (9%), diarrhea (3%) and fatigue. Toxicity analyses, as well as cost-effectiveness analyses, are ongoing, Toi said.
Subgroup analyses indicated patients benefited regardless of hormone receptor status.
“The balance of benefit and toxicity would favor the use of capecitabine in the post-neoadjuvant chemotherapy situation, but predication for the therapeutic benefits needs to be investigated further,” Toi said. – by Alexandra Todak
Reference:
Soo-Jung L, et al. Abstract S1-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-12, 2015; San Antonio.
Disclosure: The study was supported by a grant from Advanced Clinical Research Organization. Toi reports a research grant from Chugai Pharmaceutical Company.
Perspective
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Anees B. Chagpar, MD, MPH
We know that patients who achieve a pathologic complete response after neoadjuvant chemotherapy can do very well, but many patients do not achieve that outcome. Those who have residual disease are often left wondering whether they are simply chemotherapy resistant or whether there is something else that we can try.
In this study, what is exciting is that, not only did capecitabine work in terms of improving DFS, but it actually offers something to think about as additional therapy after having residual disease after neoadjuvant chemotherapy.
A lot of novel therapies are going to be coming out in this space. There are clinical trials ongoing looking at immunotherapies and this type of research — figuring out what we can do when patients do not get that pathologic complete response that everybody is searching for — is really going to be the next wave of research in terms of improving outcomes in patients with breast cancer.
Coverage for medications will follow the data. So, as we get more and more studies that are showing efficacy of these medications and showing that we can improve survival, insurance companies will be compelled to cover them.
Perspective
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Virginia Kaklamani, MD
This trial included patients who received neoadjuvant chemotherapy but have not had eradication of their breast cancer, and adjuvantly, they were able to receive 24 weeks of capecitabine. What Toi and colleagues showed was that the capecitabine improved both DFS — which was the primary endpoint of the study — and OS in this study population.
There is one major issue of reimbursement. These are patients who would be receiving chemotherapy for an extra 24 weeks. It’s an oral chemotherapy that right now is not approved by the FDA, and in this country, and I’m sure in Japan as well, patients would have a problem having insurance coverage.
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