Exemestane在乳癌的初步輔助治療上優於Tamoxifen


  September 29, 2009 (德國柏林) —根據發表於第15屆歐洲癌症組織研討會與第34屆歐洲腫瘤醫學會年會聯合研討會中的資料,使用exemestane(商品名Aromasin)輔助治療似乎比tamoxifen更有效,更能降低乳癌病患的復發。
  
  這項結論來自「Tamoxifen Exemestane Adjuvant Multinational (TEAM)」研究,是比較芳香胺酶抑制劑與tamoxifen作為初步內分泌治療效果之三個試驗中最大型的研究。
  
  分析顯示,早期侵犯性荷爾蒙受體陽性乳癌且停經的病患,使用exemestane進行初步輔助治療,在改善無病存活與降低疾病復發方面優於tamoxifen。
  
  第一作者、荷蘭Leiden大學醫學中心的外科教授Cornelis van de Velde博士表示,在2.75年時,exemestane與改善無病存活、發生遠端轉移的時間、無復發存活等有關。
  
  英國西約克夏癌症治療研究中心臨床癌症藥物與腫瘤教授、臨床主任Chris Twelves醫師表示,此一資料相當令人印象深刻。這項研究再度提出芳香胺酶抑制劑較優,加強了我們對此類製劑的運用。
  
  【TEAM試驗的分析】
  TEAM試驗世代包括了來自9個國家、9,779名停經後且有侵犯性雌激素受體陽性和/或黃體素受體陽性的早期乳癌婦女,以前瞻性方式隨機分派接受每天20mg的tamoxifen 20 mg或每天25mg的exemestane。所有病患都有完整的初步手術治療,若適合化療者也有接受化學治療。
  
  原始試驗開始於2001年,當時的初級終點是無病存活。但是,在2004年,基於「Intergroup Exemestane Study (IES)」研究結果顯示exemestane的強力利益,原始試驗做了修改。所有tamoxifen組病患換成使用exemestane,期間為2.5至3年。
  
  van de Velde博士解釋,修改的研究設計有兩個終點。第一個比較使用tamoxifen或exemestane達2.75年之病患的無病存活。第二個比較使用exemestane 5年之婦女以及使用tamoxifen之後轉用exemestane共5年之婦女的無病存活。
  
  van de Velde博士表示,目前的分析聚焦在第一個初級終點:使用tamoxifen或exemestane達2.75年之後的無病存活以及相關事件的確認。
  
  結果顯示,與tamoxifen相比,exemestane與較佳的無病存活有關(風險比[HR]為0.89;95%信心區間[CI]為0.77- 1.03;P= .12),無復發存活也較佳(HR,0.85%;95% CI,0.72- 1.00;P= .056)。在發生遠端轉移的時間方面,exemestane也較佳(HR,0.81;95% CI,0.67- 0.98;P=.028)。
  
  整體而言,exemestane組的病患局部復發、遠端轉移、對側乳癌、無復發的死亡案例少了11%。
  
  【Tamoxifen停用率高】
  在TEAM研究中,tamoxifen組停止治療的比率(29.5%;n= 1434人)高出exemestane組(18.9%;n= 926人)許多。此外,754名使用tamoxifen的病患很早就換成exemestane。
  
  van de Velde博士表示,各國的停用率不盡相同,這一點需多加注意。我們需告知病患副作用,但是也要告訴她們持續治療的助益。順從性不佳也會影響芳香胺酶抑制劑試驗的結果。
  
  沒有發生意料外的安全問題,但是使用exemestane發生關節痛、腕隧道症候群、腹瀉、高膽固醇症的機會較高;兩組發生心臟缺血與梗塞的比率相似。
  
  【IES試驗資料也顯示較優的結果】
  許多資料顯示exemestane較優,至於在轉換試驗方面,英國倫敦帝國理工學院腫瘤科主任Charles Coombes博士在會議中報告了IES的長期追蹤。TEAM研究設定在比較兩種產品的初步治療,IES則是比較使用tamoxifen 2到3年後轉成exemestane,以及維持用tamoxifen達整整5年者。
  新的長期資料證實,轉換組的無病存活顯著降低18% (HR,0.82;P= .0009),且顯示整體存活顯著延長,降低死亡風險達14% (HR,0.86;P= .04)。
  
  Coombes博士在聲明中表示,IES的這些新的長期追蹤資料顯示,轉成exemestane之病患有顯著的存活利益,優於那些繼續使用tamoxifen者;這些發現對病患和醫師一樣重要,因為再度肯定使用tamoxifen2到3年後轉成exemestane的信心。
  
  美國和歐洲已經核准停經後且雌激素受體為陽性之早期乳癌婦女,在Tamoxifen治療2到3年之後使用exemestane。
  
  TEAM和IES研究都接受exemestane之製造商輝瑞藥廠的資助。
  
  第15屆歐洲癌症組織研討會(ECCO 15)與第34屆歐洲腫瘤醫學會年會(34th ESMO)聯合研討會:摘要 2BA (TEAM研究)與5010 (IES研究)。發表於2009年9月22日。
  

Exemestane Superior to Tamoxifen as Initial Adjunct Therapy in Breast Cancer

By Roxanne Nelson
Medscape Medical News

September 29, 2009 (Berlin, Germany) — Adjuvant therapy with exemestane (Aromasin) appears to be more effective than tamoxifen in reducing disease recurrence in breast cancer patients, according to data presented here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress.

The conclusions come from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) study, the largest of 3 trials to compare the efficacy of an aromatase inhibitor with tamoxifen as initial endocrine therapy.

The analysis shows that in postmenopausal patients with early invasive hormone-receptor-positive breast cancer, initial adjuvant treatment with exemestane was superior to tamoxifen in improving disease-free survival and reducing disease recurrence.

"At 2.75 years, exemestane was associated with improved disease-free survival, time to distant metastasis, and recurrence-free survival," said lead author Cornelis van?de?Velde, MD, PhD, professor of surgery at Leiden University Medical Center in the Netherlands.

"The data are very impressive," said Chris Twelves, MD, clinical director and professor of clinical cancer pharmacology and oncology at the Institute of Cancer Therapeutics in West Yorkshire, United Kingdom. "This study is another demonstration of the superiority of [aromatase inhibitors], and does reinforce that we use them up front."

Analysis of TEAM Trial

The TEAM cohort consisted of 9779 postmenopausal patients with invasive estrogen-receptor-positive and/or progesterone-receptor-positive early breast cancer from 9 countries who were prospectively randomized to tamoxifen 20?mg/day or exemestane 25?mg/day. All patients had completed primary therapy of surgery and, if indicated, chemotherapy .

The original trial began in 2001, when the primary end point was disease-free survival. But in 2004, on the basis of results of the Intergroup Exemestane Study (IES), which showed a strong benefit for exemestane, the study was amended. All patients in the tamoxifen group were switched to exemestane at 2.5 to 3 years.

The modified study design, explained Dr. van?de?Velde, had 2 end points. The first compared disease-free survival in patients using either tamoxifen or exemestane for up to 2.75 years. The second end point compared disease-free survival in women using exemestane for 5 years with that in women using tamoxifen who switched to exemestane for a total of 5 years.

The current analysis focused on the first primary end point — disease-free survival after 2.75 years with tamoxifen or exemestane — with the censoring of events, said Dr. van?de?Velde.

Their results showed that, compared with tamoxifen, exemestane is associated with better disease-free survival (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.77?- 1.03; P?= .12) and relapse-free survival (HR, 0.85%; 95% CI, 0.72?- 1.00; P?= .056). Time to first distant metastasis was also better with exemestane (HR, 0.81; 95% CI, 0.67?- 0.98; P?= .028).

Overall, there were 11% fewer cases of local recurrence, distant metastases, contralateral breast cancer, and deaths without disease relapse for patients in the exemestane group.

Discontinuation Rates Higher for Tamoxifen

In the TEAM study, a much higher rate of patients in the tamoxifen group discontinued their treatment (29.5%; n?= 1434), than in the exemestane group (18.9%; n?= 926). In addition, 754 tamoxifen patients made an early switch to exemestane.

"Discontinuation rates varied considerably by country, and this does deserve more attention," said Dr. van?de?Velde. "We need to inform patients of the side effects, but also the benefits of continuing their treatment. Noncompliance can confound the results of [aromatase inhibitor] trials."

There were no unexpected safety issues reported, but exemestane use was associated with significantly higher incidences of arthralgia, carpal tunnel syndrome, diarrhea, and hypercholesterolemia. The incidence rate for cardiac ischemia and infarction was similar between the groups.

IES Data Also Show Superiority

More data showing superiority of exemestane, but from a switching trial, come from a long-term follow-up of the IES, and were reported at the meeting by Charles Coombes, MD, PhD, FRCP, FMedSci, head of oncology at Imperial College in London, United Kingdom. Whereas the TEAM study set out to compare initial therapy with the 2 products, the IES compared switching to exemestane after 2 to 3 years of tamoxifen with staying on tamoxifen for the full 5 years. The new longer-term data confirm a significant 18% reduction in disease-free survival in the group that switched (HR, 0.82; P?= .0009), and show a significant prolongation of overall survival, reducing the risk of dying by 14% (HR, 0.86; P?= .04).

"These new longer-term follow-up data from the IES demonstrate a significant survival benefit for patients who switched to exemestane compared with those who stayed on tamoxifen," Dr. Coombes said in a statement. "These findings are important to patients and physicians alike, as they reaffirm their confidence in switching to exemestane after 2 to 3 years on tamoxifen."

The use of exemestane after 2 to 3 years of tamoxifen therapy in postmenopausal women with estrogen-receptor-positive early breast cancer is an approved indication in both the United States and Europe.

Both the TEAM and the IES studies were funded by Pfizer, the manufacturer of exemestane.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstracts 2BA (TEAM study) and 5010 (IES study). Presented September 22, 2009.

    
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