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Gemcitabine-Capecitabine for Advanced Breast Cancer: Impressive Phase II Results
Abstract & Commentary
William B. Ershler, MD
Synopsis: In a phase II trial of capecitabine and gemcitabine for patients who had previously received an anthracycline for either as an adjuvant or for metastatic disease, overall response rate was 55% and the median time to progression was 11 months. These results were somewhat better for patients who were being treated for the first time for advanced disease (i.e., for recurrence after adjuvant therapy) when compared to those who were receiving the drugs as second line.
Source: Ciruelos EM, et al. Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: A multicenter phase II study (SOLTI 0301 trial). Annals Oncol. 2010;21:1442-1447.
Anthracyclines have assumed a primary role in the management of breast cancer, and are currently used as initial therapy either in the adjuvant or metastatic setting. Thus, clinicians frequently encounter the need to treat anthracycline-pretreated patients, and defining optimal therapy in this setting remains to be established.1 Certainly, taxanes are commonly used in anthracycline-pretreated breast cancer patients, but other agents, such as 5-fluorouracil (F-FU), vinorelbine, capecitabine, and gemcitabine also are known to have activity. Capecitabine, an orally administered prodrug of 5-FU, when used first line as a single agent for patients with advanced disease, has demonstrated response rates ranging from 25-37%.2 Similarly, gemcitabine, a pyrimadine analogue of deoxycytidine, has demonstrable activity when used in the setting of metastatic breast cancer.3 In preclinical studies, when these two drugs are used together, a synergistic anti-tumor effect has been demonstrated.4 Furthermore, several phase II studies have been conducted demonstrating the safety and efficacy of this combination in a wide range of tumors including, most notably, pancreatic cancer.5 In fact, in a retrospective report of 31 heavily pretreated breast cancer patients, an overall response rate of 10% was observed,6 whereas in a phase II trial (also in heavily pretreated patients), the overall response rate was 48.7% and the median time to progression was five months .
To study this combination further, Ciruelos and colleagues throughout Spain carried out a multicenter, phase II clinical trial on the combination of gemcitabine and capecitabine in advanced anthracycline-pretreated breast cancer patients. This was an open-label, multicenter, non-randomized, phase II trial, with the primary objective to assess overall response rate and, secondarily, to estimate time to progression, duration of response, and safety.
The study was empowered to analyze two groups: group 1, not previously treated for metastatic disease; and group 2, previously treated. A total of 76 anthracycline-pretreated breast cancer patients were enrolled 41 in group 1 and 35 in group 2.
Patients received gemcitabine 1000 mg/m2, i.v., as 30 min-infusion on days 1 and 8 every 21 days, and oral capecitabine 830 mg/m2 b.i.d., days 1–14 every 21 days. This dose and schedule was chosen on the basis of a prior study.7
The overall response rate was 61% for group 1, 48.5% for group 2, and 55.2% for the whole population. The tumor control rate (defined as the sum of overall response plus stable disease rates) was 73% for group 1, 80% for patients in group 2, and 76% for all patients. Median time to progression was 13.0 months for group 1, 8.2 months for group 2, and 11.1 months for the whole population. Most frequent grade 3–4 observed toxicities were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%), and hand–foot syndrome (16%). Only one patient presented with febrile neutropenia. No treatment-related deaths occurred. Dose delays or reductions occurred in approximately 20% of cycles, primarily because of neutropenia (most commonly at day eight of any cycle) or hand-foot syndrome.
Thus, the combination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients. Although this was not a randomized study, the response rates are quite similar to the combination of docetaxel with capecitabine.8 Also, the safety and toxicity were quite reasonable, even though there was quite a high rate of dose and schedule change. A randomized trial is in order to determine whether this regimen is actually superior to one that is taxane-based in terms of response or tolerability. Furthermore, for those patients with tumors that over-express HER-2, it is unclear to what degree the addition of trastuzumab to either of these regimens would influence the overall success of therapy.
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3. Spielmann M, et al. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60:303-307.
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8. O'Shaughnessy J, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002; 20:2812-2823.