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作者：Nick Mulcahy  
出處：WebMD醫學新聞

　　December 18, 2009（德州聖安東尼奧）－ 在預防骨質流失上，預先對以芳香酶抑制劑（AI）治療之停經後女性乳癌患者使用間斷性zoledronic acid（Zometa，諾華藥廠），比延遲治療更好。
　　
　　這是Zometa-Femara輔助加成治療試驗（Z-FAST）最終五年結果的其中一個發現，這項研究結果發表於第32屆聖安東尼奧乳癌座談會（SABCS）。
　　
　　賓州匹茲堡大學癌症中心Adam Brufsky醫師表示，這項研究是一個檢驗zoledronic acid預防這些處方AI之荷爾蒙受體陽性停經後女性骨質流失「最長的」研究；他在記者會上透過電話表示意見，因為生病致使他無法前往聖安東尼奧參加會議。
　　
　　Brufsky醫師表示，骨質流失與可能骨折是乳癌治療一個已知的併發症，這些治療包括芳香酶抑制劑。
　　
　　Zoledronic acid，是一種靜脈注射的雙磷酸鹽類藥物，在這項研究中注射15分鐘，每6個月注射一次，這是用於治療AI相關骨質流失之口服雙磷酸鹽的另一選擇。
　　
　　5年後，這些病患被隨機分派為預先治療組（共140位），其腰椎骨質密度（BMD）平均增加6.2%，相較於延遲治療組（共132位），則下降了2.4%，因此，兩種方法之間的差異為8.6%，達到統計上顯著差異（P<0.001）。
　　
　　在髖骨部位，預先治療組的BMD增加2.6%；延遲治療組下降4.1%；絕對差異達到統計上顯著的6.7%（P<0.001）。
　　
　　BMD被認為是停經後女性骨折風險的一個強烈代理標記。
　　
　　這場會議的引言人、印第安納波里斯印第安納大學醫學院的Theresa Guise醫師表示，芳香酶抑制劑在治療荷爾蒙受體陽性、初期乳癌上比tamoxifen好，但可能發生骨骼併發症。
　　
　　她總結表示，當談到阻止AI引起的骨質流失，這代表了在疾病預防上是個進步，這項研究中使用的是letrozole（Femara，諾華藥廠）。
　　
　　【次要試驗終點：骨折風險與次級再發】
　　在這項多中心研究，停經後女性如果有雌性激素受體陽性以及/或是黃體激素受體陽性乳癌（分期I至IIIA），以及髖骨及腰椎T指數-2以下即符合納入研究標準。T指數是由雙能X射線吸收計評估的骨質密度。
　　
　　在12週收納期間，所有病患都接受手術、化療、以及/或是放射線治療，且無殘餘病灶。
　　
　　所有受試者每天都口服letrozole 2.5 mg。預先組（共300位）在隨機分派後立即使用zoledronic acid。
　　
　　延遲組（共300位）基底後腰椎或整個髖骨T指標下降少於-2.0或是發生非創傷性臨床骨折。
　　
　　這項研究並未被設計偵測兩組之間骨折發生率或是疾病的顯著差異，這兩個都是次級試驗終點。
　　
　　接受預先治療病患有9.3%發生骨折（共28位），延遲治療病患則有11%（共33位）。
　　
　　這項研究收集600位研究參與者的骨折與疾病再發資料，但是僅有其中262位受試者的5年BMD數據。
　　
　　在疾病再發上，預先治療組病患事件發生率為5.3%（共16位），而接受延遲組為7%（共7位）。相較於預先治療組，延遲治療組的女性，發生遠端骨折的比例高出兩倍（9位比上19位）。
　　
　　Brufsky醫師表示，zoledronic acid是否可以改善免於疾病惡化存活率，是這些重要臨床研究的課題。AZURE研究在去年的SABCS會議發表，當時也由Medscape腫瘤學報導。再來，澳洲研究者們最近發表的數據指出，zoledronic acid改善乳癌患者免於疾病惡化存活率。
　　
　　Brufsky醫師指出，這項研究並未發現嚴重不良反應或下顎骨質壞死，確認這個藥物是安全且耐受性良好。
　　
　　Brufsky醫師擔任諾華藥廠顧問。Guise醫師擔任Amgen、Lilly、Novartis與Roche藥廠的顧問團。



Upfront Zoledronic Acid Is Best for AI-Related Bone Loss
By Nick Mulcahy
Medscape Medical News
December 18, 2009 (San Antonio, Texas) — Using intermittent zoledronic acid (Zometa, Novartis) upfront to prevent bone loss among postmenopausal women with breast cancer taking an aromatase inhibitor (AI) is better than delaying the therapy.
This is one of the findings from the final 5-year results of the Zometa-Femara Adjuvant Synergy Trial (Z-FAST), which was presented here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).
The study is the "longest running trial" testing the hypothesis that zoledronic acid prevents bone loss in these hormone-receptor-positive postmenopausal women who are prescribed an AI, said Adam Brufsky, MD, from the University of Pittsburgh Cancer Institute in Pennsylvania. He was speaking at a meeting press conference over the telephone because illness prevented him from traveling to San Antonio.
"Bone loss and potential fracture are a known complication of breast cancer therapy, including aromatase inhibitors," said Dr. Brufsky.
Zoledronic acid, an intravenous bisphosphonate given in the study over 15 minutes every 6 months, is an alternative to an oral bisphosphonate for the treatment of AI-related bone loss.
At 5 years, patients randomized to the upfront treatment group (n?= 140) had a mean increase in bone mineral density (BMD) of 6.2% in their lumbar spine, compared with a 2.4% decrease in the delayed treatment group (n?= 132). Thus, the absolute difference between the 2 approaches was 8.6%, which is statistically significant (P?< .001).
  
Dr. Theresa Guise  
In the hip area, with upfront treatment, the BMD increase was 2.6%; with delayed treatment, there was a decrease of 4.1%. The absolute difference was a statistically significant 6.7% (P?< .001).
BMD is considered a strong surrogate marker for fracture risk in postmenopausal women.
"This is a very important study," said Theresa Guise, MD, from the Indiana University School of Medicine in Indianapolis, who moderated the press conference, "because aromatase inhibitors are superior to tamoxifen [in the treatment of hormone-receptor-positive, early-stage breast cancer] and skeletal complications can occur."
This represents a step forward in disease prevention.
"This represents a step forward in disease prevention," she summarized, referring to the inhibition of bone loss from an AI, which in this study was letrozole (Femara, Novartis).
Secondary End Points: Fracture Rates and Secondary Recurrences
In this multicenter study, postmenopausal women were eligible if they had estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer (stages?I to IIIA) and hip and lumbar T?scores of –2 or more. The T?score refers to bone density assessed by dual-energy x-ray absorptiometry.
All of the patients underwent surgery, chemotherapy, and/or radiation within 12 weeks of enrolment and had no residual disease.
All participants received letrozole 2.5?mg orally daily. The upfront group (n?= 300) received zoledronic acid immediately after random assignment.
The delayed group (n?= 300) received zoledronic acid when either postbaseline lumbar spine or total hip T?score decreased to less than –2.0 or a nontraumatic clinical fracture occurred.
Although the study was not designed to detect a significant difference in the fracture rate or disease between treatment groups, both were secondary end points.
Fractures occurred in 9.3% (n = 28) of the patients treated upfront and in 11% (n?= 33) of the patients receiving delayed treatment.
There were fracture and disease recurrence data for all 600 study participants, whereas there were only full 5-year BMD data for 262 participants.
In terms of disease recurrence, events occurred in 5.3% (n?= 16) of the patients treated upfront and in 7% (n?= 7) of the patients receiving delayed treatment. Twice as many women in the delayed-treatment group as in the upfront group had distant recurrence (19 vs 9).
Whether or not zoledronic acid can improve disease-free survival is the subject of a major clinical trial, AZURE, said Dr. Brufsky. Early results from the AZURE trial were presented at last year's SABCS conference and covered by Medscape Oncology at that time. Also, Austrian investigators recently published data indicating that zoledronic acid improves disease-free survival in breast cancer.
There were no serious renal events and no osteonecrosis of the jaw, which confirmed that the drug was safe and well tolerated, said Dr. Brufsky.
Dr. Brufsky reports serving as a consultant to Novartis. Dr. Guise reports serving on the advisory boards of Amgen, Lilly, Novartis, and Roche.
32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract?4083. Presented December?11, 2009.