Bevacizumab是用來控制卵巢癌的新方法


  【24drs.com】兩篇第3期試驗指出,bevacizumab(Avastin,Genentech/Roche藥廠)可延緩末期卵巢癌的病程,讓醫師有一個新的治療選項,這兩篇試驗都登載於12月29日的新英格蘭醫學期刊。
  
  根據這兩篇試驗資料,歐盟最近核准bevacizumab用於治療末期卵巢癌女性。
  
  這兩篇試驗有一些不同之處,但是都探討將bevacizumab納入卵巢癌第一線治療、加到標準化療。
  
  賓州費城Fox Chase癌症中心婦女癌症中心主任Robert A. Burger醫師在記者會中表示,Bevacizumab阻斷了對卵巢癌惡化很重要的血管內皮生長因子。
  
  Burger醫師是「Gynecologic Oncology Group (GOG) study 0218」這篇研究的主要研究者,這篇1,873名病患的研究在美國、加拿大、南韓、日本共336個地點進行。
  
  在GOG0218研究中,末期上皮卵巢癌病患,於carboplatin和paclitaxel化療後使用bevacizumab治療到最多10個月,可延長無惡化存活期(PFS)中位數達3.8個月。
  
  特別地是,單純化療組的PFS中位數為10.3個月,化療加bevacizumab組則是14.1個月,延長的這段期間,全程使用bevacizumab組的惡化或死亡風險比(HR)為0.717 (95%信心區間[CI]為0.625 - 0.824;P < .001),追蹤中位數為17.4個月。
  
  Burger醫師總結表示,這個方法可視為卵巢癌治療的第三個重要元素,將bevacizumab加到目前的標準化療與減積手術(兩篇研究的所有研究對象都先接受了手術)。這為我們提供了一個控制疾病的新方法。
  
  第二篇研究中,36個月時,PFS(限制平均值)在標準治療組為20.3個月,標準治療加bevacizumab組為21.8個月(加入bevacizumab的惡化或死亡HR為0.81;95% CI,0.70 - 0.94;P = .004)。整體而言,英國Leeds大學Timothy Perren醫師形容此治療差異是中度結果。
  
  這篇「Gynecologic Cancer InterGroup International Collaboration on Ovarian Neoplasms 7 (ICON7)」試驗包括了1,528名婦女、在全球共263個地點進行。ICON7試驗的研究者指出,研究第12個月時的治療效果最大,與bevacizumab治療結束時一致。事實上,在24個月時效果消失,使研究者在36個月時使用新的統計方法、限制平均差異,這個方法適用於「非比例風險」。
  
  加入bevacizumab在第12個月時最有效的這個事實,比標準治療改善了15.1% (95% CI,10.7 - 19.5)的PFS,使研究者推論可以繼續維持治療,他們表示,研究結果支持在12個月後延長治療的可能性,或許治療到疾病惡化、改善後續結果。
  
  GOG0218之研究者形容bevacizumab是「第一線治療選項」,但也指出需要更多研究評估bevacizumab在這類患者的使用。他們指出需要更適當的治療期間與時機,檢視成本效益,更重要的是,瞭解可能用來預測效果和副作用的腫瘤因素或宿主生物因素,最終目標是降低疾病發病率及死亡率。
  
  ICON7和GOG這兩篇研究有許多不同之處。ICON7研究納入之末期癌症病患(70%)並無可見的殘留病灶,有些是高風險、早期疾病(9%),GOG0218研究中,全部都是末期的第3期(不完整切除、有一些殘留病灶)或第4期,GOG0218的病患全部都是上皮疾病,而ICON7則是90%如此。
  
  同樣重要的是,在ICON7研究中,使用的是半數劑量的bevacizumab(7.5 mg/kg),而GOG0218研究則是用15 mg/kg劑量於比較短的維持期(分別是12 vs 16療程)。
  
  值得一提的是,ICON7研究中,高惡化風險病患的預後和GOG研究的所有病患相似。Perren醫師等人寫道,ICON7研究的bevacizumab組觀察到PFS有3.6個月的改善(限制平均值),和GOG-0128研究相似。他們指出,bevacizumab的效果較佳對於那些預後比較不好的病患而言,是令人鼓勵的。
  
  兩篇研究的主要結果也有差異。GOG0218研究中,主要終點是PFS,但也有追蹤存活率。進行這次新分析時(追蹤中位數17.4個月),76.3%的病患依舊存活,整體死亡率沒有顯著差異。
  
  ICON7研究中,PFS是次級結果,主要結果則是整體死亡率;這些還不是最終資料,預計在2013年時才提出。不過,在他們更新的分析中,研究者報告了1年時的Kaplan-Meier估計比率,bevacizumab組為92%、標準治療組為86% (HR,0.85;95% CI,0.69 - 1.04;P = .11)。
  
  Bevacizumab在這兩篇試驗中都沒有影響化療給藥。不過,如同ICON7研究作者所說的,該藥擴大了毒性效果。更要注意的是,bevacizumab增加了高血壓和腸穿孔風險。例如,在GOG0218研究中,因高血壓而需要治療的比率,全程使用bevacizumab組(22.9%)高於單純化療組(7.2%)。需要治療的胃腸道穿孔比率在對照組和全程使用bevacizumab組分別是1.2%和2.6%。
  
  在GOG組中,所有病患都接受了靜脈注射paclitaxel(劑量175 mg/m2)加carboplatin(AUC值6)的化療、共6個療程,加上研究療法(安慰劑或bevacizumab)從第2療程到第22療程,每個療程有3週的期間。
  
  這篇研究實際上有三組:一組單純只有化療,另外兩組分別有不同療程的bevacizumab。
  
  控制組是在第2-22療程進行化療加安慰劑,另一組,也就是bevacizumab起始治療組則是在第2-6療程進行化療加bevacizumab (15 mg/kg body weight),在第7-22療程則是加入安慰劑。第三組,全程使用bevacizumab組則是化療後在第2-22療程加入bevacizumab。
  
  Bevacizumab起始治療組在PFS的改善程度小於全程使用bevacizumab組。
  
  ICON7研究中,病患被隨機指派接受carboplatin (AUC值5或6)與paclitaxel (175 mg/m2體表面積),每3週給予、進行6個療程,或者接受這個處方加上bevacizumab (7.5 mg/kg體重),每3週給予、進行5或6個療程。持續另外12個療程或到病情惡化為止。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_idno=6696&x_classno=0&x_chkdelpoint=Y
  

Bevacizumab Is a 'New Way to Control' Ovarian Cancer

By Nick Mulcahy
Medscape Medical News

December 28, 2011 — Two phase 3 trials have demonstrated that bevacizumab (Avastin, Genentech/Roche) slows the progression of ovarian cancer in women with advanced disease, and thus offers clinicians a new class of treatment. Both trials were published in the December 29 issue of the New England Journal of Medicine.

Data from these 2 trials formed the basis of the recent approval in Europe of bevacizumab for use in women with advanced ovarian cancer.

The complementary trials differed in a number of ways, but both investigated the addition of bevacizumab to standard chemotherapy in the first-line treatment of ovarian cancer.

"Bevacizumab blocks the growth factor [vascular endothelial growth factor], which is important in the process of ovarian cancer progression," said Robert A. Burger, MD, one of the bevacizumab investigators, in a press statement. He is director of the Women's Cancer Center at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Dr. Burger was the lead investigator of the Gynecologic Oncology Group (GOG) study 0218. The 1873-patient study took place at 336 sites located primarily in the United States, but also in Canada, South Korea, and Japan.

In the GOG0218 study, the use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy extended the median progression-free survival (PFS) by 3.8 months in patients with advanced epithelial ovarian cancer.

Specifically, the median PFS was 10.3 months in the chemotherapy-alone control group and 14.1 months in the group that received chemotherapy plus bevacizumab for a prolonged maintenance period. This prolonged, "bevacizumab-throughout" group had a hazard ratio (HR) for progression or death of 0.717 (95% confidence interval [CI], 0.625 - 0.824; P < .001). The median follow-up was 17.4 months.

"This approach can be looked upon as a third major component of treatment for ovarian cancer," summarized Dr. Burger, referring to the use of bevacizumab in addition to the current standard of chemotherapy and debulking surgery. (All of the women in both studies first received surgery.) "This represents a new way for us to control the disease," he added.

This represents a new way for us to control the disease.

In the second study, PFS (restricted mean) at 36 months was 20.3 months with standard therapy and 21.8 months with standard therapy plus bevacizumab (HR for progression or death with bevacizumab added, 0.81; 95% CI, 0.70 - 0.94; P = .004). Overall, the treatment difference was described as "modest" by the study authors, led by Timothy Perren, MD, from the University of Leeds in the United Kingdom.

This study, known as the Gynecologic Cancer InterGroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, involved 1528 women and took place at 263 international sites.

The ICON7 investigators noted that the treatment effect was maximized earlier in the study, at 12 months, coinciding with the end of the bevacizumab treatment. In fact, the effect disappeared at 24 months, which led the investigators to use the novel statistical method of restricted mean difference for their calculations at 36 months. The method accounts for "nonproportional hazards."

The fact that the addition of bevacizumab was most effective at 12 months, with a resounding 15.1% (95% CI, 10.7 - 19.5) improvement in PFS compared with standard therapy, led the investigators to speculate about possible continuous maintenance treatment. They said that the findings raised the "possibility that prolonged therapy beyond 12 months, perhaps until disease progression, might further improve outcome."

The GOG0218 investigators called bevacizumab a "front-line treatment option," but also said that much more work is needed in evaluating bevacizumab in this setting. They cited the need to optimize duration and timing of treatment, examine cost-effectiveness, and "perhaps most important, identify potential tumor or host biologic factors predictive of efficacy and adverse events with the ultimate goal of decreasing morbidity and mortality from this disease."

Earlier data from both studies have been previously reported by Medscape Medical News: Data from ICON7 were reported from the American Society of Clinical Oncology 2011 Annual Meeting and at the 35th European Society for Medical Oncology Congress, and data from GOG0128 were reported from the American Society of Clinical Oncology 2010 Annual Meeting.

Differences in the 2 Studies

The ICON7 trial differed from the GOG trial in a number of ways.

The ICON7 study enrolled patients with advanced-stage cancer (70%) who had no visible residual disease, as well as some patients with high-risk, early-stage disease (9%). In the GOG0218 study, all of the patients had advanced disease: stage 3 (incompletely resectable, and thus some residual disease) or stage 4. All of the women in GOG0218 had epithelial disease; 90% in ICON7 did so.

Also important is that in the ICON7 study, half the dose of bevacizumab was used (7.5 mg/kg vs 15 mg/kg in the GOG0218 study) for a shorter maintenance period (12 vs 16 cycles).

Notably, the prognosis for patients at high risk for progression in the ICON7 study was similar to that for all patients in the GOG study. A 3.6-month (restricted mean) improvement in PFS was observed with bevacizumab in ICON7, "similar to that seen in the GOG-0128 study," write Dr. Perren and coauthors. "The apparently greater effect of bevacizumab in patients with a poor prognosis is encouraging," they add.

Overall Survival and Adverse Events

The primary outcomes were also different in the 2 studies. In GOG0218, the primary endpoint was PFS, but the trial is also tracking survival. At the time of the new analysis (median follow-up, 17.4 months), 76.3% of the patients were still alive, with no significant differences in overall survival.

In ICON7, PFS is a secondary outcome and overall survival is the primary outcome; these data are not yet final and are due in 2013. However, in their updated analysis, the investigators report that Kaplan-Meier estimated rate of 1-year survival was 92% in the bevacizumab group and 86% in the standard therapy group (HR, 0.85; 95% CI, 0.69 - 1.04; P = .11).

Bevacizumab did not affect the delivery of chemotherapy in either trial. However, the drug did, as the ICON7 authors worded it, "expand the range of toxic effects." Most notably, bevacizumab increased hypertension and bowel perforation. For instance, in the GOG0218 study, the rate of hypertension requiring medical therapy was higher in the bevacizumab-throughout group (22.9%) than in the control chemotherapy group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2% and 2.6% of patients in the control group and the bevacizumab-throughout group, respectively.

Study Designs

In GOG, all patients received chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg/m2 body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment (either placebo or bevacizumab) for cycles 2 through 22, with each cycle having 3 weeks' duration.

The study actually had 3 groups: 1 with chemotherapy alone and 2 with differing lengths of bevacizumab.

The control treatment was chemotherapy with placebo added in cycles 2 through 22. Another group, known as "bevacizumab-initiation" treatment, was chemotherapy with bevacizumab (15 mg/kg body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22.

The third group, known as "bevacizumab-throughout" treatment was chemotherapy with bevacizumab added in cycles 2 through 22.

The bevacizumab-initiation group had less improvement in PFS than the more treatment-intensive bevacizumab-throughout group.

In ICON7, patients were randomly assigned to receive carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg/m2 body-surface area), given every 3 weeks for 6 cycles, or to receive this regimen plus bevacizumab (7.5 mg/kg body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease.

GOG0128 was supported by Roche/Genentech and the National Cancer Institute. ICON7 was supported by Roche/Genentech and the National Institute for Health Research, through the National Cancer Research Network in the United Kingdom. The lead authors of both GOG0128 and ICON7, as well as some of their coauthors, have disclosed financial relationships with the study sponsor, Roche. The lead authors also report relationships with other pharmaceutical companies.

N Engl J Med. 2011;365:2473-2496.

    
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