Vinorelbine是HER-2陽性進展性乳癌偏好的化學治療

毒性是關鍵,而非療效。

【24drs.com】對於HER-2陽性轉移或局部進展性乳癌女性而言,什麼是併用trastuzumab時最好的化學治療藥物?
  
  根據斯堪的納維亞研究人員進行的新研究結果,並沒有在療效數據中發現答案,而是在毒性結果中找到。
  
  就那點來說,研究人員發現,在一項第三期第一線治療的臨床研究中,當與trastuzumab(Herceptin)合併使用時,vinorelbine(Navelbine)的副作用顯著少於docetaxel(Taxotere);以惡化所需時間測量的療效,兩種療程的效果相當。
  
  這項「Herceptin Plus Navelbine or Taxotere(HERNATA)」試驗比較了284位來自丹麥、瑞典、以及挪威的女性,研究結果首次發表於歐洲乳癌會議2010年,現在於1月20日發表於臨床腫瘤學期刊上。
  
  研究後的主編評論作者表示,研究結果反映出內科腫瘤學家已經在臨床執業中發現這些。
  
  撰寫這篇主編評論的兩位腫瘤內科醫師,麻州波士頓達那-法柏癌症機構的Nancy U. Lin醫師與Eric Winer醫師寫到,許多臨床醫師選擇合併使用trastuzumab與vinorelbine,或比較少見的,合併capecitabine用於第一線治療,因為taxane等替代藥物一般而言毒性比較大。
  
  有鑑於毒性較低,且未能證實docetaxel比vinorelbine好,他們相信這項研究紮紮實實建立了trastuzumab加上vinorelbine作為HER-2陽性轉移乳癌患者的第一線治療,甚至是偏好的選項。
  
  這項研究由來自丹麥哥本哈根Rigshospitalet的Michael Andersson醫師領導,他們比較沒那麼肯定,他們在文獻中這樣表達他們的結論:vinorelbine加上trastuzumab應被視為是比較好、風險/好處平衡的第一線替代選項。
  
  選擇第一線化學治療藥物,治療效果可能不是最重要的,但毒性確是更重要的;換句話說,作者們間接聲援vinorelbine更勝taxanes類藥物,包括docetaxel。
  
  根據Lin醫師與Winer醫師指出,目前只有taxanes類藥物中的paclitaxel獲美國藥物管理局(FDA)核准與trastuzumab併用於轉移乳癌患者。Docetaxel由歐盟核准與trastuzumab合併使用治療HER-2轉移乳癌。Vinorelbine並未獲得這兩個官方機構核准用於這個適應症。然而,國家綜合癌症網絡將vinorelbine與paciltaxel(合併或不合併carboplatin)、docetaxel與capecitabine都列為該適應症偏好的第一線治療藥物。
  
  主編們相信不需要更多研究進一步定義在這個情況下哪一種化學治療是最好的;他們寫到,以我們的觀點,玩不同化學治療藥物之間的搶椅遊戲能夠獲得的資訊並不多。
  
  他們附帶表示,trastuzumab是個很好的平衡者,讓其他特定選擇化學治療變成是次要的。
  
  Lin與Winer醫師表示,研究中需要的是將這些研究擴展為「個人化與標靶性」治療;他們需要引起更多目光。
  
  【研究發現】
  這項研究由羅氏與賽諾菲安萬特藥廠贊助,收納HER-2陽性轉移或局部進展性乳癌患者,這些患者過去都沒有接受化學治療或針對HER-2治療他們的進展性疾病。
  
  總共有284位患者被隨機分派接受docetaxel 100 mg/m2每3週1次(共143位)或vinorelbine(30 mg/m2或35 mg/m2,根據機構事前定義的偏好)在第1天、第8天投予,每21天為一個週期(共141位);所有病患每3週接受1次trastuzumab治療。
  
  這些治療持續到疾病惡化、毒性無法耐受或是病患退出。
  
  主要試驗終點是惡化所需時間,這項研究結果未達統計上顯著差異:使用docetaxel患者惡化所需平均時間為12.4個月,而使用vinorelbine為15.3個月(危險比值[HR]為0.94;95%信賴區間[CI]為0.71-1.25;P=0.67)。
  
  研究作者們解釋,偏好vinorelbine的療效預後令人驚訝。
  
  他們寫到,在構思這項研究時,據信vinorelbine加上trastuzumab合併使用,相較於docetaxel與trastuzumab,在療效上並沒有比較差。
  
  大部分的次要試驗終點,包括整體存活率,也沒有顯著差異;使用docetaxel患者的整體存活時間為35.7個月,vinorelbine平均為38.8個月(HR為1.01;95% CI為0.71-1.42;P=0.98)。
  
  其中一個例外是,治療失敗所需時間,投給docetaxel一道負面的光芒;使用docetaxel相較於vinorelbine,治療失敗所需時間顯著較短(5.6相較於7.7個月;HR為0.50;95% CI為0.38-0.64;P<0.0001)。
  
  作者們與主編們皆表示,兩藥物的毒性是最不一樣的地方;接受docetaxel治療患者,相較於vinorelbine,因為毒性而停藥的機率顯著較高(20.1%相較於6.5%;P<0.001)。
  
  相較於vinorelbine,以docetaxel治療顯著較多治療相關第三級與第四級中性球低下發熱(36.0%相較於10.1%)、白血球低下(40.3%相較於21.0%)、感染(25.1%相較於13.0%)、發燒(4.3%相較於0.0%)、神經病變(30.9%相較於3.6%)、指甲異常(7.9%相較於0.7%)與水腫(6.5%相較於0.0%)。
  
  Andersson醫師接受羅氏與賽諾菲安萬特藥廠的演講費,兩家公司都贊助這項研究。部分研究作者報告與該公司或其他公司有資金上的往來。Lin醫師接受Genetech、格蘭素威康、百靈佳、Infinity藥廠的研究經費。Winter醫師接受Genetech公司的研究經費。

Vinorelbine 'Preferred' Chemo in HER2-Positive Advanced Breast Cancer

By Nick Mulcahy
Medscape Medical News

January 26, 2011 — What's the best chemotherapy to use in combination with trastuzumab in women with HER2-positive metastatic and locally advanced breast cancer?

The answer is not found in the efficacy data; instead, it is found in toxicity results, according to the Scandinavian authors of a new study on the subject.

On that score, the investigators found, in a phase 3 trial of first-line therapies, that vinorelbine (Navelbine) had significantly fewer adverse effects than docetaxel (Taxotere) when each was combined with trastuzumab (Herceptin). Efficacy, measured by time to progression, was comparable between the 2 regimens.

Results from the Herceptin Plus Navelbine or Taxotere (HERNATA) trial, which comprised 284 women from Denmark, Sweden, and Norway, were first presented at the European Breast Cancer Conference in 2010 and have now been published in the January 20 issue of the Journal of Clinical Oncology.

The results reflect what medical oncologists have been finding out on their own in clinical practice, suggest the authors of an editorial that accompanies the study.

"Many clinicians choose to partner trastuzumab with vinorelbine or, less frequently, capecitabine" in this first-line setting because the taxane alternatives are generally more toxic, say 2 breast cancer oncologists, Nancy U. Lin, MD, and Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, who wrote the editorial.

This study firmly establishes . . . trastuzumab plus vinorelbine as an acceptable, and even preferred, option.

"Given the more favorable toxicity profile and the failure to conclude that docetaxel is superior to vinorelbine," they write, "we believe this study firmly establishes the role of trastuzumab plus vinorelbine as an acceptable, and even preferred, option for the first-line treatment of patients with HER2-positive metastatic breast cancer."

The study authors, led by Michael Andersson, MD, from Rigshospitalet in Copenhagen, Denmark, are less definitive. They conclude their paper by saying that "vinorelbine plus trastuzumab should be considered as an alternative first-line option with a favorable risk/benefit balance."

But they also write that "the choice of a first-line chemotherapy drug . . . may not be important . . . regarding treatment efficacy, but it certainly is important in terms of toxicity." In other words, the authors indirectly champion vinorelbine over taxanes, including docetaxel.

According to Dr. Lin and Dr. Winer, only the taxane paclitaxel is currently approved by the US Food and Drug Administration for use in combination with trastuzumab in HER2-positive metastatic breast cancer. Docetaxel is approved for use in combination therapy by the European Medicines Agency. Vinorelbine is approved by neither agency in this setting at this point. However, the National Comprehensive Cancer Network lists vinorelbine — along with paclitaxel (with or without carboplatin), docetaxel, and capecitabine — as preferred first-line agents in this setting.

The editorialists believe that more research studies are not needed to further define which chemotherapy is optimal in this setting. "In our view, little will be gained by playing musical chairs with chemotherapeutic agents," they write.

Trastuzumab is the "great equalizer," they add, "rendering the specific choice of chemotherapy secondary."

What is needed in research is an expansion of investigations into "individualized and targeted" therapies; they need to "claim the limelight," say Dr. Lin and Dr. Winer.

Study Findings

The study, which was supported by Roche and Sanofi-Aventis, enrolled patients with HER2-positive metastatic or locally advanced breast cancer who had not received previous chemotherapy or HER2-targeted therapy for the treatment of their advanced disease.

A total of 284 patients were randomized to treatment with either docetaxel 100 mg/m2 once every 3 weeks (n =1 43) or vinorelbine (30 mg/m2 or 35 mg/m2, according to institutional predefined preference) on days 1 and 8 of a 21-day cycle (n = 141). Trastuzumab was administered to all patients once every 3 weeks.

Treatment was continued until progression, intolerable toxicity, or patient withdrawal.

The primary study end point was time to progression, which was not statistically significantly different: the median for docetaxel was 12.4 months and for vinorelbine was 15.3 months (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.71 to 1.25; P = .67).

This efficacy outcome favoring vinorelbine was surprising, explain the study authors.

"At the time of conception of the study, it was believed that the vinorelbine plus trastuzumab combination was inferior to docetaxel plus trastuzumab in terms of efficacy," they write.

There was no difference in most of the secondary end points, including overall survival. Median overall survival was 35.7 months for docetaxel and 38.8 months for vinorelbine (HR, 1.01; 95% CI, 0.71 to 1.42; P = .98).

The one exception to this — time to treatment failure — cast docetaxel in a negative light. Median time to treatment was significantly shorter for docetaxel than for vinorelbine (5.6 vs 7.7 months; HR, 0.50; 95% CI, 0.38 to 0.64; P < .0001).

Toxicity is where the 2 agents were most different, say both the authors and the editorialists. More patients in the docetaxel group than in the vinorelbine group discontinued therapy because of toxicity (20.1% vs 6.5%; P < .001).

With docetaxel, compared with vinorelbine, there were also significantly more treatment-related grade 3 to 4 febrile neutropenia (36.0% vs 10.1%), leucopenia (40.3% vs 21.0%), infection (25.1% vs 13.0%), fever (4.3% vs 0.0%), neuropathy (30.9% vs 3.6%), nail changes (7.9% vs 0.7%), and edema (6.5% vs 0.0%).

Dr. Andersson reports receiving honoraria from Roche and Sanofi-Aventis, the 2 companies that sponsored the study. Some of the study coauthors reported financial ties to these companies and others. Dr. Lin reports receiving research funding from Genentech, GlaxoSmithKline, Boehringer Ingelheim, and Infinity Pharmaceuticals. Dr. Winer reports receiving research funding from Genentech.

J Clin Oncol. 2010;29:251-253, 264-271.

    
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