Metastatic Breast Cancer

Several studies presented at the San Antonio Breast Cancer Symposium support the use of capecitabine as an attractive chemotherapeutic option for patients with metastatic breast cancer because of the drug's convenience, tolerability, and positive effects on quality of life. Because many patients with metastatic breast cancer have been heavily pretreated and are considered refractory or resistant to anthracyclines and taxanes; in this palliative setting, it is important to select a therapy that will be well tolerated and not compromise patients' functioning. The research presented at the meeting show that capecitabine is beneficial as a single agent and can be safely and effectively combined with taxanes in anthracycline-pretreated patients and gemcitabine in anthracycline- and taxane-pretreated patients. The research presented showed that capecitabine is beneficial as a single agent and can be safely and effectively combined with taxanes in anthracycline-pretreated patients and gemcitabine in anthracycline- and taxane-pretreated patients. Capecitabine vs Vinorelbine An exploratory study suggests that capecitabine, an oral fluoropyrimidine designed to deliver fluorouracil preferentially to tumor tissue, was the better choice compared with vinorelbine, a vinca alkaloid that binds to tubulin and prevents cell division by interfering with the synthesis of DNA and RNA. Capecitabine was associated with improved tolerability, convenience, and prolonged time to survival compared with vinorelbine in heavily pretreated patients with metastatic breast cancer. The study, conducted at two Canadian centers, was designed to compare capecitabine with vinorelbine in metastatic breast cancer patients previously treated with anthracyclines and taxanes. Lead author Sunil Verma, MD, a medical oncologist at Sunnybrook & Women's Health Sciences Center and Associate Professor at the University of Toronto, said she and her colleagues had the impression that capecitabine was the better drug, and Phase II studies had also shown this. “There can be considerable neuropathy when vinorelbine is given after a taxane,” Dr. Verma noted. “Capecitabine is an oral drug that is less toxic than vinorelbine and provides better quality of life, because patients can take it at home.” The patients treated with single-agent vinorelbine were younger, had larger and more receptor-negative primary tumors, had a higher number of positive lymph nodes, and were more heavily pretreated compared with those treated with single-agent capecitabine. However, their tumors were more likely to be lower grade and HER-2/neu negative compared with the tumors of patients in the capecitabine group. Patients were able to stay on therapy longer with capecitabine; the mean duration of therapy was 129 days with capecitabine and 65 days with vinorelbine. Longer period of treatment was associated with improved survival. The median overall survival was 188 days for capecitabine and 102 days for vinorelbine. One-year survival was 28% in the capecitabine group and 15% in the vinorelbine group. In the small group of patients who received capecitabine followed by vinorelbine, the median duration of therapy was 110 days (138 days with capecitabine, 87 days with vinorelbine); the median overall survival time was 390 days, and the one-year survival rate was 46%. Dr. Verma said that it made sense that this group did so well, “because if they responded well to capecitabine, they would respond well to the next drug.” Although this study was suggestive of the superiority of capecitabine compared with vinorelbine, a formal, randomized trial is of course still needed to establish this with certainty, and Dr. Verma said the Canadian investigators are currently discussing this. Quality of Life Another study at the meeting found that single-agent capecitabine significantly improved quality of life from baseline in patients with metastatic breast cancer. The open-label study included 611 patients treated with standard capecitabine at 1,250 mg/m2 twice daily on Days 1–14 every three weeks. Almost all the quality-of-life domains assessed improved with capecitabine, reported lead author Jose Getulio M. Segalla, MD, of Fundacao Amaral Carvalho in Jau Sao Paulo, Brazil. These domains were global health status, physical functioning, role functioning, and social functioning. Improvements were also seen in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation, and diarrhea, as well as body image, sexual enjoyment, and future perspective. Some 70% to 80% of patients in the study experienced improved or maintained quality of life with capecitabine treatment for most of the domains studied, Dr. Segalla reported, adding that treatment with capecitabine allowed patients with metastatic breast cancer to maintain a normal lifestyle and the drug thus had a direct impact on quality of life. Combined Capecitabine/, Gemcitabine Capecitabine/gemcitabine was found to be an active combination in a Phase II study reported by Gumersindo Perez-Manga, MD, of the Hospital Gregorio Maranon in Madrid, and to have a favorable toxicity profile. The study included 42 patients with a mean age of 55 and adequate organ function. Fifty-five percent were hormone receptor positive, 36% were hormone receptor negative, and 9% had unknown status. Patients were treated with gemcitabine at 800 mg/m2 intravenously on Days 1 and 8 and capecitabine at 1,500 mg/m2/day orally b.i.d. over 14 days. Cycles were repeated until disease progression. Capecitabine plus gemcitabine was active in 36 of the patients evaluable for efficacy, and there was an overall response in 12 patients (29%); a complete response in five (12%), and partial response in seven (17%). Grade 3 or 4 neutropenia was observed in 25 patients (59%). Non-hematologic toxicity was mild, and three patients (7%) had Grade 3 or 4 hand-foot syndrome. Combination & Sequential Therapy Interim analysis of a randomized, prospective, Phase III study conducted by the Mexican Oncology Study Group found that combination therapy with capecitabine plus paclitaxel or docetaxel (XP or XT) and sequential therapy with capecitabine followed by a taxane (Xfitaxane) were highly effective in patients with anthracycline-pretreated metastatic breast cancer. High overall response rates were seen in 206 evaluable patients; this was related to the good prognosis of enrolled patients, with predominantly soft tissue metastases at single sites, said lead author Laura Torrecillas, MD, of Servicio de Oncologia, ISSSTE, in Mexico City. Although the overall response rates trended higher in the combination therapy group, the difference between the groups was not statistically significant. The overall response rates were 73% for XP, 76% for XP, and 58% for Xfitaxane. Progressive disease was observed in 18%, 11%, and 19% of patients, respectively. Safety was favorable in all three-treatment arms. The most common Grade 3 and 4 adverse event was alopecia in the combination arms; other Grade 3 and 4 events were infrequent and rarely occurred when capecitabine was given first in sequential therapy. Dr. Torrecillas said that although sequential therapy as used in this trial may be more convenient and safer than with combination therapy, the combination may still be preferable because it gives all patients the same chance to respond to both agents. ‘Not Yet Fully Developed’ “These studies continue to show the flexibility and efficacy of capecitabine as a palliative agent for Stage IV breast cancer,” commented a breast cancer expert not involved in the studies, Clifford Hudis, MD, Chief of the Breast Cancer Medical Service at Memorial Sloan-Kettering Cancer Center. Still, he noted, “there may be better ways to give capecitabine. I don't think this drug is fully developed. In fact, our team is now exploring novel doses and schedules for capecitabine predicted by laboratory models to be even more effective.”

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