SAN ANTONIO—Results of a large phase III trial show that combining oral capecitabine(Drug information on capecitabine) (Xeloda) with docetaxel(Drug information on docetaxel) (Taxotere) significantly improved overall survival, time to disease progression, and response rates over docetaxel alone in women with anthracycline-resistant metastatic breast cancer.
"This combination regimen will give us a powerful new option to treat women with metastatic breast cancer," Joyce O’Shaughnessy, MD, said at the 23rd Annual San Antonio Breast Cancer Symposium. Dr. O’Shaughnessy, co-director of breast cancer research, Baylor-Sammons Cancer Center, Dallas, presented the results at a poster session along with Svetislava J.Vukelja, MD, of US Oncology, Tyler, Texas.
Dr. O’Shaughnessy noted that this is the first clinical trial to demonstrate a survival advantage with a cytotoxic combination over a standard monotherapy in this patient population.
Capecitabine, an oral fluoropyrimidine, is a prodrug of 5-fluorouracil (5-FU) that is first broken down in the liver and, finally, by thymidine phosphorylase (TP) at the tumor site. TP is overexpressed in tumor tissue, resulting in more tumor-selective delivery of 5-FU and some sparing of normal cells.
The rationale for the trial was that capecitabine and docetaxel have different mechanisms of action and no overlapping of key toxicities. In addition, docetaxel upregulates expression of TP, and preclinical animal studies have shown synergistic antitumor effects with the two agents.
A total of 511 patients were enrolled from 75 centers in 16 countries. Patients had locally advanced or metastatic breast cancer that had progressed while on anthracycline-based chemotherapy or relapsed after anthracycline therapy, given in the metastatic setting or as adjuvant or neoadjuvant therapy. Prior paclitaxel(Drug information on paclitaxel) (Taxol) was permitted, but prior docetaxel was not.
Patients were randomized to 3-weekly cycles of combination therapy with oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14, plus IV docetaxel 75 mg/m2, on day 1, or full-dose IV docetaxel 100 mg/m2 as monotherapy on day 1. Patients with an objective response or stable disease after 6 weeks of therapy received further treatment until disease progression or unacceptable toxicity.
About one third of the patients in each group received study therapy as first-line chemotherapy for metastatic disease, and about one half as second-line treatment. "This was a very highly treated population," Dr. Vukelja told ONI.
In patients who received the capecitabine/docetaxel combination, the median time to disease progression was 6.1 months vs 4.2 months with docetaxel monotherapy (see table at right). Objective tumor response rates were significantly better with the combination than with monotherapy (42% vs 30%). The median duration of response was similar in both groups (7.2 and 6.9 months).
Overall median survival was also significantly better in patients receiving the combination: 13.7 months vs 11.1 months with monotherapy. Survival rates at 12 months were 56% vs 46%, respectively, and at 18 months, 35% and 28%.
Quality of life showed a trend in favor of the combination arm but was not significant, Dr. Vukelja said.
Safety Evaluation
The majority of treatment-related adverse events in both arms were mild to moderate in intensity; these occurred in 83% of the combination arm and 86% of the monotherapy arm.
The incidence of grade 3-4 treatment-related adverse events was 78% in the combination arm and 64% in the monotherapy arm. Life-threatening grade 4 treatment-related adverse events were less frequent with the combination (25% vs 30% with monotherapy).
The patients who received the combination regimen experienced more gastrointestinal toxicities and hand-foot syndrome. Hand-foot syndrome can be well controlled provided that it is treated promptly, Dr. Vukelja said. Only one case of hand-foot syndrome resulted in hospitalization. She emphasized that patients must be educated to watch for early symptoms of the syndrome.
Patients who received docetaxel monotherapy had a higher incidence of neutropenic fever, myalgia, arthralgia, and pyrexia.
"Given the significantly superior efficacy achieved by combining docetaxel with capecitabine and the manageable side-effect profile, this combination provides clear benefits compared with docetaxel monotherapy in patients with metastatic breast cancer previously exposed to anthracyclines," Dr. O’Shaughnessy concluded.
