桓兴医讯

北京桓兴医院,桓兴医院,桓兴肿瘤医院

推荐文章

您当前位置:桓兴肿瘤医院 > 桓兴医讯 > 桓兴医讯 奥拉帕尼联合化疗治疗复发性铂敏感卵巢癌:一项随机II
桓兴医讯 奥拉帕尼联合化疗治疗复发性铂敏感卵巢癌:一项随机II
文章来源:北京市朝阳区桓兴肿瘤医院 点击数: 发布时间:2014-12-05 08:50
《柳叶刀肿瘤分册》2014年12月4日在线先发
奥拉帕尼联合化疗治疗复发性铂敏感卵巢癌:一项随机II期临床试验
背景
多聚ADP核糖聚合酶抑制剂奥拉帕尼在铂敏感、再复发的、BRCA1/BRCA2基因突变阳性或阴性的高分期浆液性卵巢癌患者中表现出抗肿瘤活性。本研究的目的是对比评估奥拉帕尼加化疗序贯奥拉帕尼单药与单纯化疗在铂敏感的、复发的、高分期的的浆液性卵巢癌患者中的有效性和耐受性。
方法
在这项随机、开放标签、2期临床研究中,铂敏感、复发的、高分期浆液性卵巢癌成年患者已经接受过三个月以上的以铂类为基础的化疗,无进展期至少6个月,患者随机化接受奥拉帕尼(200mg胶囊,每日2次,口服,d1-10,21天为1周期)联合紫杉醇(175mg/m2,静脉给药,d1)+卡铂(AUC=4 mg/ml.min,根据本卡尔弗特式,静脉给药,d1),然后序贯奥拉帕尼单药维持治疗(400mg胶囊,2次/日,持续给药),直到进展(即奥拉帕尼加化疗组),或者接受紫杉醇(175mg/m2,d1)+卡铂(AUC=4 mg/ml.min,d1),则无进一步的处理(即单纯化疗组)。通过交互式语音应答系统来完成随机化分组,通过既往接受含铂方案治疗的数目和上一次铂治疗方案之后疾病进展时间进行分层。主要终点是无进展生存期,依据标准实体瘤疗效评价版本1.1进行评估,通过意向性治疗来分析。预先设定的探索性分析包括BRCA突变状态,回顾性评估疗效。这项研究已经在ClinicalTrials.gov注册,编号NCT01081951。
结果
在2010年2月12日至7月30日之间,有来自12个国家、43个研究性网站的173名患者被纳入研究,其中162人符合条件,患者被随机分配到两个治疗组(81名分配到奥拉帕尼加化疗组,81名分配到单纯化疗组)。这些随机的患者,有156名患者进入联合期治疗(奥拉帕尼加化疗组81人,单纯化疗组75人),有121名患者进入维持阶段或无进一步治疗阶段(奥拉帕尼加化疗组66人,单纯化疗组55人)。107名患者为BRCA突变状态(无论是在基线或追溯决定):41人(38%)有BRCA基因突变(奥拉帕尼加化疗组20人,单纯化疗组21人)。奥拉帕尼加化疗组的无进展生存期显著延长(中位PFS为12.2个月[95%CI 9.7-15.0]),单纯化疗组(中位PFS为9.6个月[95%CI 9.1-9.7)(HR 0.51[95%CI 0.34-0.77]; P=0.0012),尤其是在BRCA基因突变患者中(HR 0.21[0.08-0.55 ];P=0.0015)。在联合阶段,奥拉帕尼加化疗组比单纯化疗组更频繁报道、发生率10%以上的不良事件为脱发(81人中有60人[74%] VS 75人中有44人 [59%]),恶心(56[69%] VS 43[57%]),中性粒细胞减少(40[49%] VS 29[39%]),腹泻(34[42%] VS 20[27%]),头痛(27[33%] VS 7[9%]),周围神经病变(25[31%] VS 14[19%])和消化不良(21[26%] VS 9[12%]);大多数为轻度至中度。在联合阶段,最常见的3级以上的不良事件是中性粒细胞减少(在81名奥拉帕尼加化疗组患者中有35例[43%]VS 75名单纯化疗组中的26例[35%])和贫血(7[9%] VS 5[7%])。严重不良反应报告:81例奥拉帕尼加化疗组患者中有12例(15%)和75名单纯化疗组患者中有16例(21%)。
讨论
对比紫杉醇+卡铂单纯化疗,奥拉帕尼加紫杉醇或卡铂序贯奥拉帕尼单药维持可显著提高患者的无进展生存期,尤其是BRCA突变患者可获得最大的临床获益,并且有一个可以接受的和可控制的耐受性。
北京桓兴肿瘤医院 桓兴医讯编译组 田中秋
2014年12月4日 星期四
The Lancet Oncology, Early Online Publication, 4 December 2014
doi:10.1016/S1470-2045(14)71135-0
Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial
Background
The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer.
Methods
In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1—10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m2 on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, numberNCT01081951, and has been completed.
Findings
Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12•2 months [95% CI 9•7—15•0]) than in the chemotherapy alone group (median 9•6 months [95% CI 9•1—9•7) (HR 0•51 [95% CI 0•34—0•77]; p=0•0012), especially in patients with BRCA mutations (HR 0•21 [0•08—0•55]; p=0•0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group.
Interpretation
Olaparib plus paclitaxel or carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile.
Funding
AstraZeneca.

标签:

北京桓兴肿瘤医院,北京朝阳区桓兴肿瘤医院,桓兴肿瘤医院,北京桓兴医院,北京专科肿瘤医院 北京桓兴肿瘤医院,北京朝阳区桓兴肿瘤医院,桓兴肿瘤医院,北京桓兴医院,北京专科肿瘤医院