Pharmacy & Therapeutics - March 2008 - (Page 149) Meeting Highlights: Breast Cancer Symposium initial therapy. Among patients with normal baseline T-scores who received up-front Zometa, T-scores dropped to below –2 in 5% of the women. By contrast, in the delayed-therapy group, T-scores dropped to below –2 in 23% to 24% of the women (P = 0.0024). In patients with low baseline T-scores (i.e., –1 to –2), T-scores dropped to below –2 in 3% to 4% of patients receiving initial therapy and in 15% to 20% of patients receiving delayed therapy. Although Z-FAST was not powered to assess fracture rates, Dr. Brufsky said that the overall fracture rates were 5.7% with initial therapy and 6.3% with delayed treatment. He called the finding of a 3.5% rate of disease recurrence in the up-front group, compared with 6.9% in the delayed group, “exploratory” and “somewhat intriguing.” There were no reports of osteonecrosis of the jaw, a concern in other bisphosphonate trials, and Zometa was generally safe and well tolerated with “no surprises,” Dr. Brufsky said. He concluded: “Up-front administration of Zometa led to increased lumbar spine and total hip bone mineral density with no differences in fracture rates, as compared with delayed Zometa treatment.” Combined Therapy: Ixempra plus Xeloda Presenter: Hope Rugo, MD, Clinical Professor of Medicine at University of California, San Francisco, Comprehensive Cancer Center, San Francisco, Calif. Compared with capecitabine (Xeloda, Roche) alone, the combination of ixabepilone (Ixempra, BMS) plus Xeloda nearly doubled progression-free survival among a subset of women with highly treatment-resistant “triple negative” breast cancer, according to Dr. Rugo. Ixempra, a novel semisynthetic analogue of epothilone B, causes cell cycle arrest and apoptosis of actively dividing cancer cells by stabilizing microtubules. Women who are estrogen and progesterone receptor–negative and HER-2–negative (ER/PR/HER-2–) comprise 10% to 20% of those with early breast cancer, but they also comprise a much higher proportion of those with metastatic disease, which is associated with poor response and short survival with standard chemotherapy, Dr. Rugo said. Dr. Rugo and her colleagues hypothesized that because Ixempra overcomes mechanisms that cause resistance to taxanes and anthracyclines, it might overcome the resistance commonly experienced by these very-poor-risk patients. The open-label study included 752 women (median age, 52.5 years), 25% of whom had triple-negative status (ER–/PR–/HER-2–) with metastatic breast cancer that was resistant to taxanes and that had been pretreated with or was resistant to anthracyclines. The patients were randomly assigned to undergo a 21-day cycle of IV Ixempra at a dose of 40 mg/m2 on day 1 plus oral Xeloda at 2,000 mg/m2 on days 1 to 14 or to receive Xeloda alone at 2,500 mg/m2 on days 1 to 14. The primary endpoint was progression-free survival. Median progression-free survival was 4.1 months among the 91 women with triple-negative status who were receiving Ixempra/Xeloda and 2.1 months among 96 triple-negative women receiving Xeloda alone. The overall response rate with these two agents was 27%, compared with 9% for Xeloda alone. In the overall population, progression-free sur vival was 5.8 months with Ixempra/ Xeloda and 4.2 months with Xeloda alone. Response rates were 35% with the combination and 14% with Xeloda monotherapy. In the combination arm, grade 3 and 4 neutropenia (68%) and sensor y neuropathy (21.1%) were manageable with dose adjustments. In the overall population, most grade 3 and 4 peripheral neuropathy was reversible, Dr. Rugo said; in 89% of patients, it resolved to grade 1 or to baseline measures in a median of six weeks. Grade 3 and 4 febrile neutropenia was reported in 5% of patients receiving the combination therapy. Dr. Rugo commented in an interview: “Our idea is to move this drug much earlier in the treatment of breast cancer to potentially overcome resistance sooner and perhaps treat with curative intent.” The trial findings, she suggested, confirm the activity of Ixempra in patients with triple-negative status and with anthracycline/taxane-resistant metastatic breast cancer. I Aromatase Inhibitors and Tamoxifen Presenter: James Mansell, MD, Western Infirmary, Glasgow, Scotland A study that examined the incidence, type, and timing of breast cancer recurrence supports an initial strategy of aromatase inhibitors for women with postmenopausal estrogen receptor–positive (ER+) status, according to Dr. Mansell. He noted that beneficial results from trials of adjuvant aromatase inhibitors have led to the widespread use of these agents, but the continued use of tamoxifen (e.g., Nolvadex, AstraZeneca) as an initial strategy might leave women more vulnerable to recurrence. In major trials, women were switched from tamoxifen to an aromatase inhibitor at a mean of 2.5 years. Distant recurrences, the prevalent recurrence type in these trials, are known to be a significant predictor of breast cancer–related deaths. Dr. Mansell evaluated 4,245 ER+ women 50 years of age and older (median age, 62 years) with early-stage breast cancer in the United Kingdom over a median follow-up period of 60 months. At two years, the recurrence rate peaked at 4.2%. Most of these recurrences were at distant sites (3.2%). At 2.5 years, the cumulative recurrence rate was 6.2% (4.5% of recurrences were distant), and at five years, the rate was 13.9%; 9.8% of recurrences were distant, 2.7% were locoregional, and 1.3% were contralateral. These findings suggest that the distant recurrence is indeed the predominant type in the first two years in postmenopausal women with early stage ER+ breast cancer, said Dr. Mansell, and disease recurs even with treatment with the antiestrogen agent tamoxifen. He concluded: “We would recommend starting an up-front aromatase inhibitor for all postmenopausal women with ER+ breast cancer, apart from those at particularly low risk of recurrence. There is no reason to wait for 2.5 years.” Vol. 33 No. 3 • March 2008 • P&T® 149
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