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作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　September 23, 2009 — 根據一項於9月20日線上發表於Lancet的多中心、第三期、開放標記、隨機分派控制組研究結果顯示，一種「劑量密集」化學治療療程可能改善進展性卵巢癌患者預後。
　　
　　日本東京國家癌症中心醫院的Noriyuki Katsumata與其同事們寫到，Paclitaxel與carboplatin每三個星期投予一次是進展性卵巢癌的標準治療。透過加入其他藥物來改善病患預後的期待是落空的。因此，我們比較paclitaxel與carboplatin傳統療程，與劑量密集每週療程，使用於罹患進展性卵巢癌女性的效果。
　　
　　在日本的85個中心，總共有637位罹患第二期到第四期上皮卵巢癌、輸卵管癌、或原發性腹膜癌的患者被收納到這項研究中，透過電腦產生的隨機分派表分派接受6個週期的傳統（共320位）或劑量密集（共317位）化學治療療程。
　　
　　傳統療程包括paclitaxel（180 mg/m2；靜脈輸注3小時）加上carboplatin（曲線下面積為6 mg/ml/min），在第1天投予，每21天為一個週期。劑量密集療程在第1、8、15天投予paclitaxel（80 mg/m2；靜脈輸注1小時），加上第1天投予carboplatin，每21天為一個週期。遵循意向分析原則，主要試驗終點為免於疾病惡化存活率。
　　
　　在637位納入研究的病患中，631位適合接受治療且被收納到意向分析族群中（312位分派到接受劑量密集療程、319位接受傳統療程）。相較於標準療程組，劑量密集組的免於疾病惡化存活時間中位數顯著較長（28.0個月[95%信賴區間（CI）為22.3-25.4]，相較於17.2個月[95% CI為15.7-21.1]；危險比值[HR]為0.71；95% CI為0.58-0.88；P=0.0015）。在3年時，劑量密集組的整體存活率為72.1%，傳統治療組則是65.1%（HR為0.75[95% CI為0.57-0.98]；P=0.03）。
　　
　　在劑量密集組共有165位病患提早停止治療，而在傳統治療組則有117位病患。劑量密集組病患因為藥物毒性而退出的人數顯著較多（113人相較於69人），但是其他退出試驗原因，在兩組之間並沒有顯著差異。中性球低下是最常觀察到的不良事件（劑量密集組，312位病患中有286位[92%]；傳統治療組中，314位有276位[88%]）。相較於傳統治療組，劑量密集組發生第三級與第四級貧血頻率顯著較高（214位[69%]相較於137位[44%]；P<0.0001）。其他毒性作用在兩組之間的發生頻率並沒有不同。
　　
　　研究作者們寫到，相較於傳統療程，每週劑量密集投予paclitaxel與carboplatin可以顯著改善存活，代表這對於進展性上皮卵巢癌女性來說是個新的治療選擇。
　　
　　這項研究的限制包括劑量密集組根據研究計劃完成治療的病患不到一半。除此之外，這項研究並未被設計評估治療時間長短與臨床預後之間的關係。
　　
　　在隨後的主編評論中，來自土桑市亞歷桑納癌症中心的Michael A. Bookman稱這項是個重要的第三期臨床研究，且將會影響日後的研究設計，使標準照護進化。
　　
　　Bookman博士寫到，免於疾病惡化的成熟數據是高度顯著的，且一般可預測卵巢癌患者的整體存活。婦科癌症團隊成員已經計劃進行確認性試驗，評估每週一次的靜脈投予，加上或未加上bevacizumab。使用這樣的劑量密集療程應該根據病患個別狀況以及進展性卵巢癌患者的其他治療選擇，包括腹腔內治療、術前治療或是替換成docetaxel來決定。
　　
　　必治妥藥廠贊助這項研究，與另外三位試驗作者也有不同資金上的往來。Bookman博士擔任必製妥藥廠、格蘭素威康、禮來藥廠、賽諾菲安萬特、諾華、輝瑞、亞培藥廠與百靈佳藥廠的特別顧問。

"Dose-Dense" Chemotherapy Regimen May Improve Outcomes in Advanced Ovarian Cancer

By Laurie Barclay, MD
Medscape Medical News

September 23, 2009 — A "dose-dense" chemotherapy regimen may improve outcomes in advanced ovarian cancer, according to the results of a multicenter, phase 3, open-label, randomized controlled trial reported online September 20 in The Lancet.

"Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma," write Noriyuki Katsumata, from the National Cancer Center Hospital in Tokyo, Japan, and colleagues. "Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer."

At 85 centers in Japan, 637 patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were enrolled and assigned by computer-generated randomization sequence to receive 6 cycles of either a conventional (n = 320) or dose-dense (n = 317) chemotherapy regimen.

The conventional regimen consisted of paclitaxel (180 mg/m2; 3-hour intravenous infusion) plus carboplatin (area under the curve, 6 mg/mL/minute), given on day 1 of a 21-day cycle. The dose-dense regimen was paclitaxel (80 mg/m2; 1-hour intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle. Analysis was by intention to treat, with a main study outcome of progression-free survival.

Of the 637 enrolled patients, 631 were eligible for treatment and were included in the intention-to-treat population (312 assigned to the dose-dense regimen and 319 to the conventional regimen). Compared with the conventional treatment group, the dose-dense treatment group had longer median progression-free survival (28.0 months [95% confidence interval (CI), 22.3 – 35.4] vs 17.2 months [95% CI, 15.7 – 21.1]; hazard ratio [HR], 0.71; 95% CI, 0.58 – 0.88; P = .0015). At 3 years, overall survival was 72.1% in the dose-dense regimen group compared with 65.1% in the conventional treatment group (HR, 0.75; 95% CI, 0.57 – 0.98; P = .03).

Early discontinuation of treatment occurred in 165 patients in the dose-dense regimen group and in 117 patients in the conventional regimen group. Withdrawal because of toxicity was higher in the dose-dense regimen group (113 vs 69), but reasons for dropout were otherwise balanced between the groups. Neutropenia was the most frequently observed adverse event (dose-dense regimen, 286 [92%] of 312 patients; conventional regimen, 276 [88%] of 314 patients). Compared with the conventional treatment group, the dose-dense treatment group had a higher frequency of grade 3 and 4 anemia (214 [69%] vs 137 [44%]; P < .0001). Other toxic effects occurred with similar frequencies in both groups.

"Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer," the study authors write.

Limitations of this study include completion of treatment according to the study protocol by less than half the patients assigned to the dose-dense regimen. In addition, this study was not designed to evaluate the association between the duration of treatment and clinical outcomes.

In an accompanying comment, Michael A. Bookman, from the Arizona Cancer Center, Tucson, calls this an important phase 3 trial that will affect future trial design and evolving standards of care.

"The mature data for progression-free survival are highly significant and are generally predictive of overall survival in ovarian cancer," Dr. Bookman writes. "Confirmatory trials are planned within member groups of [the Gynecologic Cancer Intergroup] to assess once-per-week intravenous dosing, with and without bevacizumab. The use of such dose-dense therapy should be decided on an individual basis together with other options for women with advanced-stage ovarian cancer, including intraperitoneal therapy, neoadjuvant treatment, or substitution of docetaxel."

Bristol-Myers Squibb supported this study and has various financial relationships with 3 of the study authors. Dr. Bookman has served on ad hoc advisory boards for Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, sanofi-aventis, Novartis, Pfizer, Abbott Pharmaceuticals, and Boehringer Ingelheim.

Lancet. Published online September 20, 2009.