12月21日，《柳叶刀·肿瘤学》(Lancet Oncology)在线发表的一项Ⅱ期临床研究"Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study"显示，血管内皮生长因子受体(VEGF)阻滞剂阿柏西普(aflibercept)可在晚期卵巢癌患者中预防恶性腹水复发。
在这项双盲研究中，McGill大学和犹太总医院的Walter H. Gotlieb博士及其同事从比利时、加拿大、匈牙利、印度、以色列、英国和美国的23个研究中心纳入对4类(中位数)化疗产生抗性的晚期卵巢上皮癌女患者，大部分患者为浆液性癌和低分化癌，既往出现复发性恶性腹水，并且每个月需进行4次穿刺来缓解症状。患者随机接受静脉注射阿柏西普治疗(n=29)或安慰剂处置(n=26)，每2周治疗1次，持续至少60 d，但不超过6个月。6个月时，允许患者交叉接受开放性治疗。
在主要终点上(至重复穿刺的时间)，阿柏西普组明显长于安慰剂组(55 vs. 23 d)。阿柏西普组无穿刺生存期也显著长于安慰剂组(42 vs. 18 d)。值得注意的是，阿柏西普组2例患者在6个月的治疗期间不需要重复穿刺。阿柏西普组治疗开始后60 d内的中位穿刺次数为2次(范围：0~9次)，明显少于安慰剂组的4次(范围：0~17次)。此外，阿柏西普组在腹痛、腹胀、腹部不适和活动受限方面的改善大于安慰剂组。2组在总生存和无进展生存方面均无显著差异。
阿柏西普组所有患者均出现晚期腹腔疾病的常见不良反应，主要为恶心、呕吐、腹泻、疲劳、无力、周围水肿、呼吸困难和咳嗽。安慰剂组除了2例患者之外，其余所有患者均出现这些不良反应。阿柏西普组患者更常出现可能与VEGF阻滞治疗相关的潜在严重不良反应，包括静脉血栓栓塞、高血压、蛋白尿和肠穿孔。阿柏西普组的治疗相关死亡例数(4例vs. 0例)和致死性胃肠道穿孔例数(3例vs. 1例)均多于安慰剂组。阿柏西普组所有3例肠穿孔均在治疗早期(第1或第2个治疗周期)出现，2例在疾病进展的情况下出现，其中1例患者新近出现2次肠梗阻，另1例出现浸润乙状结肠的深部肿块。
阿柏西普组6例死亡与癌症进展无关：1例死于可能与研究药物有关的疑似肺栓塞，其余5例分别死于呼吸困难、肠穿孔、肺炎、吸入性肺炎和不明原因。相比之下，安慰剂组有2例患者分别死于脓毒症和吸入性肺炎。阿柏西普组4例患者和安慰剂组1例患者出现3~4级肝功能异常。
在随刊述评中，德国弗莱堡大学的Gerhild Becker博士和Hubert E. Blum博士指出，该研究表明阿柏西普能够有效预防腹水复发，但在缓解症状的同时可能导致肠穿孔等可危及生命的不良反应，因此需权衡利弊，通过仔细筛选患者或可降低此类穿孔的风险。然而，在推广阿柏西普用于治疗恶性腹水之前，尚需开展进一步研究以比较不同治疗方案在临床实践中的有效性(Lancet Oncol. 2011 [doi:10.1016/S1470-2045(11)70394-1])。
该研究获赛诺菲肿瘤事业部资助。Gotlieb博士声明与赛诺菲安万特公司存在联系，其他研究者声明与多家药企存在联系。（生物谷Bioon.com）
doi:10.1016/S1470-2045(11)70338-2
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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.
