12月21日,，《柳葉刀·腫瘤學(xué)》(Lancet Oncology)在線發(fā)表的一項(xiàng)Ⅱ期臨床研究"Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study"顯示,，血管內(nèi)皮生長(zhǎng)因子受體(VEGF)阻滯劑阿柏西普(aflibercept)可在晚期卵巢癌患者中預(yù)防惡性腹水復(fù)發(fā)。
在這項(xiàng)雙盲研究中,，McGill大學(xué)和猶太總醫(yī)院的Walter H. Gotlieb博士及其同事從比利時(shí)、加拿大、匈牙利,、印度,、以色列、英國(guó)和美國(guó)的23個(gè)研究中心納入對(duì)4類(中位數(shù))化療產(chǎn)生抗性的晚期卵巢上皮癌女患者,，大部分患者為漿液性癌和低分化癌,，既往出現(xiàn)復(fù)發(fā)性惡性腹水，并且每個(gè)月需進(jìn)行4次穿刺來(lái)緩解癥狀,?；颊唠S機(jī)接受靜脈注射阿柏西普治療(n=29)或安慰劑處置(n=26)，每2周治療1次,，持續(xù)至少60 d,，但不超過(guò)6個(gè)月。6個(gè)月時(shí),，允許患者交叉接受開(kāi)放性治療,。
在主要終點(diǎn)上(至重復(fù)穿刺的時(shí)間)，阿柏西普組明顯長(zhǎng)于安慰劑組(55 vs. 23 d),。阿柏西普組無(wú)穿刺生存期也顯著長(zhǎng)于安慰劑組(42 vs. 18 d),。值得注意的是，阿柏西普組2例患者在6個(gè)月的治療期間不需要重復(fù)穿刺,。阿柏西普組治療開(kāi)始后60 d內(nèi)的中位穿刺次數(shù)為2次(范圍：0~9次),，明顯少于安慰劑組的4次(范圍：0~17次)。此外,，阿柏西普組在腹痛,、腹脹、腹部不適和活動(dòng)受限方面的改善大于安慰劑組,。2組在總生存和無(wú)進(jìn)展生存方面均無(wú)顯著差異,。
阿柏西普組所有患者均出現(xiàn)晚期腹腔疾病的常見(jiàn)不良反應(yīng)，主要為惡心,、嘔吐,、腹瀉、疲勞,、無(wú)力,、周圍水腫、呼吸困難和咳嗽,。安慰劑組除了2例患者之外,，其余所有患者均出現(xiàn)這些不良反應(yīng)。阿柏西普組患者更常出現(xiàn)可能與VEGF阻滯治療相關(guān)的潛在嚴(yán)重不良反應(yīng),，包括靜脈血栓栓塞,、高血壓,、蛋白尿和腸穿孔。阿柏西普組的治療相關(guān)死亡例數(shù)(4例vs. 0例)和致死性胃腸道穿孔例數(shù)(3例vs. 1例)均多于安慰劑組,。阿柏西普組所有3例腸穿孔均在治療早期(第1或第2個(gè)治療周期)出現(xiàn),，2例在疾病進(jìn)展的情況下出現(xiàn)，其中1例患者新近出現(xiàn)2次腸梗阻,，另1例出現(xiàn)浸潤(rùn)乙狀結(jié)腸的深部腫塊,。
阿柏西普組6例死亡與癌癥進(jìn)展無(wú)關(guān)：1例死于可能與研究藥物有關(guān)的疑似肺栓塞，其余5例分別死于呼吸困難,、腸穿孔,、肺炎、吸入性肺炎和不明原因,。相比之下,，安慰劑組有2例患者分別死于膿毒癥和吸入性肺炎。阿柏西普組4例患者和安慰劑組1例患者出現(xiàn)3~4級(jí)肝功能異常,。
在隨刊述評(píng)中,，德國(guó)弗萊堡大學(xué)的Gerhild Becker博士和Hubert E. Blum博士指出，該研究表明阿柏西普能夠有效預(yù)防腹水復(fù)發(fā),，但在緩解癥狀的同時(shí)可能導(dǎo)致腸穿孔等可危及生命的不良反應(yīng),，因此需權(quán)衡利弊，通過(guò)仔細(xì)篩選患者或可降低此類穿孔的風(fēng)險(xiǎn),。然而,，在推廣阿柏西普用于治療惡性腹水之前，尚需開(kāi)展進(jìn)一步研究以比較不同治療方案在臨床實(shí)踐中的有效性(Lancet Oncol. 2011 [doi:10.1016/S1470-2045(11)70394-1]),。
該研究獲賽諾菲腫瘤事業(yè)部資助,。Gotlieb博士聲明與賽諾菲安萬(wàn)特公司存在聯(lián)系，其他研究者聲明與多家藥企存在聯(lián)系,。（生物谷Bioon.com）
doi:10.1016/S1470-2045(11)70338-2
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PMID:
Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study
Dr Walter H Gotlieb MD a , Frederic Amant MD b, Suresh Advani MD c, Chanchal Goswami MD d, Hal Hirte MD e, Diane Provencher MD f, Naresh Somani MD g, S Diane Yamada MD h, Jean-Francois Tamby MD i, Ignace Vergote MD b
Background
Targeting of VEGF is a potential therapeutic option in patients with malignant ovarian ascites. We present the final results of a multicentre study of the efficacy and safety of aflibercept, a potent inhibitor of both VEGF and placental growth factor, in the treatment of malignant ascites.
Methods
In this double-blind, placebo-controlled, parallel-group, phase 2 study, patients with advanced chemoresistant ovarian cancer and recurrent symptomatic malignant ascites were randomly assigned (1:1) via an interactive voice response system to either intravenous aflibercept (4 mg/kg every 2 weeks) or placebo, stratified by interval of time (≤2 weeks vs >2 weeks) between the two most recent paracenteses before randomisation. Patients participated in the double-blind period (during which patients, investigators, and sponsor personnel were masked to treatment assignment) until they had a repeat paracentesis and for at least 60 days, and could also participate in an optional open-label period during which all patients received aflibercept. The primary efficacy endpoint was time to repeat paracentesis based on response during the double-blind period alone, and was analysed in the intention-to-treat population with censoring of patients who did not have a repeat paracentesis as of the last day of the double-blind period. Safety analyses included both double-blind and open-label periods. This study is registered at ClinicalTrials.gov, number NCT00327444.
Findings
55 patients with a median of four (range two to 11) previous lines of chemotherapy were randomly assigned to receive placebo (n=26) or aflibercept (n=29). Mean time to repeat paracentesis was significantly longer with aflibercept than with placebo (55·1 [SE 7·3] vs 23·3 [7·7] days; difference 31·8 days, 95% CI 10·6—53·1; p=0·0019). In the aflibercept group, two patients did not need a repeat paracentesis during 6 months of double-blind treatment. The most common grade 3 or 4 treatment-emergent adverse events were dyspnoea (six [20%] aflibercept vs two [8%] placebo), fatigue or asthenia (four [13%] vs 11 [44%]), and dehydration (three [10%] vs three [12%]). The frequency of fatal gastrointestinal events was higher with aflibercept (three intestinal perforations) than with placebo (one intestinal fistula leading to sepsis).
Interpretation
This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit—risk balance should be thoroughly discussed for each patient.
