Jung Jae Hung, Gudeloglu Ahmet, Kiziloz Halil, Kuntz Gretchen M, Miller Alea, Konety Badrinath R, Dahm Philipp
Department of Urology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon, Korea, South, 26426.
Cochrane Database Syst Rev. 2017 Sep 12;9(9):CD011864. doi: 10.1002/14651858.CD011864.pub2.
BACKGROUND: Electromotive drug administration (EMDA) is the use of electrical current to improve the delivery of intravesical agents to reduce the risk of recurrence in people with non-muscle invasive bladder cancer (NMIBC). It is unclear how effective this is in comparison to other forms of intravesical therapy. OBJECTIVES: To assess the effects of intravesical EMDA for the treatment of NMIBC. SEARCH METHODS: We performed a comprehensive search using multiple databases (CENTRAL, MEDLINE, EMBASE), two clinical trial registries and a grey literature repository. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The last search was February 2017. SELECTION CRITERIA: We searched for randomised studies comparing EMDA of any intravesical agent used to reduce bladder cancer recurrence in conjunction with transurethral resection of bladder tumour (TURBT). DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, extracted data, assessed risk of bias and rated quality of evidence (QoE) according to GRADE on a per outcome basis. MAIN RESULTS: We included three trials with 672 participants that described five distinct comparisons. The same principal investigator conducted all three trials. All studies used mitomycin C (MMC) as the chemotherapeutic agent for EMDA. 1. Postoperative MMC-EMDA induction versus postoperative Bacillus Calmette-Guérin (BCG) induction: based on one study with 72 participants with carcinoma in situ (CIS) and concurrent pT1 urothelial carcinoma, we are uncertain (very low QoE) about the effect of MMC-EMDA on time to recurrence (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.64 to 1.76; corresponding to 30 more per 1000 participants, 95% CI 180 fewer to 380 more). There was no disease progression in either treatment arm at three months' follow-up. We are uncertain (very low QoE) about serious adverse events (RR 0.75, 95% CI 0.18 to 3.11). 2. Postoperative MMC-EMDA induction versus MMC-passive diffusion (PD) induction: based on one study with 72 participants with CIS and concurrent pT1 urothelial carcinoma, postoperative MMC-EMDA may (low QoE) reduce disease recurrence (RR 0.65, 95% CI 0.44 to 0.98; corresponding to 147 fewer per 1000 participants, 95% CI 235 fewer to 8 fewer). There was no disease progression in either treatment arm at three months' follow-up. We are uncertain (very low QoE) about the effect of MMC-EMDA on serious adverse events (RR 1.50, 95% CI 0.27 to 8.45). 3. Postoperative MMC-EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance: based on one study with 212 participants with pT1 urothelial carcinoma of the bladder with or without CIS, postoperative MMC-EMDA with sequential BCG may result (low QoE) in a longer time to recurrence (hazard ratio (HR) 0.51, 95% CI 0.34 to 0.77; corresponding to 181 fewer per 1000 participants, 95% CI 256 fewer to 79 fewer) and time to progression (HR 0.36, 95% CI 0.17 to 0.75; corresponding to 63 fewer per 1000 participants, 95% CI 82 fewer to 24 fewer). We are uncertain (very low QoE) about the effect of MMC-EMDA on serious adverse events (RR 1.02, 95% CI 0.21 to 4.94). 4. Single-dose, preoperative MMC-EMDA versus single-dose, postoperative MMC-PD: based on one study with 236 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC-EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.47, 95% CI 0.32 to 0.69; corresponding to 247 fewer per 1000 participants, 95% CI 341 fewer to 130 fewer) for a median follow-up of 86 months. We are uncertain (very low QoE) about the effect of MMC-EMDA on time to progression (HR 0.81, 95% CI 0.00 to 259.93; corresponding to 34 fewer per 1000 participants, 95% CI 193 fewer to 807 more) and serious adverse events (RR 0.79, 95% CI 0.30 to 2.05). 5. Single-dose, preoperative MMC-EMDA versus TURBT alone: based on one study with 233 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC-EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.40, 95% CI 0.28 to 0.57; corresponding to 304 fewer per 1000 participants, 95% CI 390 fewer to 198 fewer) for a median follow-up of 86 months. We are uncertain (very low QoE) about the effect of MMC-EMDA on time to progression (HR 0.74, 95% CI 0.00 to 247.93; corresponding to 49 fewer per 1000 participants, 95% CI 207 fewer to 793 more) or serious adverse events (HR 1.74, 95% CI 0.52 to 5.77). AUTHORS' CONCLUSIONS: While the use of EMDA to administer intravesical MMC may result in a delay in time to recurrence in select patient populations, we are uncertain about its impact on serious adverse events in all settings. Common reasons for downgrading the QoE were study limitations and imprecision. A potential role for EMDA-based administration of MMC may lie in settings where more established agents (such as BCG) are not available. In the setting of low or very low QoE for most comparisons, our confidence in the effect estimates is limited and the true effect sizes may be substantially different from those reported here.
背景:电动药物灌注(EMDA)是利用电流来改善膀胱内药物的递送,以降低非肌层浸润性膀胱癌(NMIBC)患者的复发风险。与其他形式的膀胱内治疗相比,其效果尚不清楚。 目的:评估膀胱内EMDA治疗NMIBC的效果。 检索方法:我们使用多个数据库(CENTRAL、MEDLINE、EMBASE)、两个临床试验注册库和一个灰色文献库进行了全面检索。我们检索了相关出版物的参考文献列表和摘要汇编。我们没有设置语言限制。最后一次检索时间为2017年2月。 选择标准:我们检索了比较任何用于降低膀胱癌复发风险的膀胱内药物的EMDA与经尿道膀胱肿瘤切除术(TURBT)联合使用的随机研究。 数据收集与分析:两位综述作者独立筛选文献、提取数据、评估偏倚风险,并根据GRADE对每个结局按证据质量(QoE)进行评级。 主要结果:我们纳入了三项试验,共672名参与者,描述了五种不同的比较。所有三项试验均由同一主要研究者进行。所有研究均使用丝裂霉素C(MMC)作为EMDA的化疗药物。1. 术后MMC-EMDA诱导与术后卡介苗(BCG)诱导:基于一项纳入72例原位癌(CIS)并发pT1尿路上皮癌患者的研究,我们对MMC-EMDA对复发时间的影响不确定(证据质量非常低)(风险比(RR)1.06,95%置信区间(CI)0.64至1.76;相当于每1000名参与者中多30例,95%CI少180例至多380例)。在三个月的随访中,两个治疗组均无疾病进展。我们对严重不良事件的影响不确定(证据质量非常低)(RR 0.75,95%CI 0.18至3.11)。2. 术后MMC-EMDA诱导与MMC被动扩散(PD)诱导:基于一项纳入72例CIS并发pT1尿路上皮癌患者的研究,术后MMC-EMDA可能(证据质量低)降低疾病复发率(RR 0.65,95%CI 0.44至0.98;相当于每1000名参与者中少147例,95%CI少235例至少8例)。在三个月的随访中,两个治疗组均无疾病进展。我们对MMC-EMDA对严重不良事件的影响不确定(证据质量非常低)(RR 1.50,95%CI 0.27至8.45)。3. 术后MMC-EMDA序贯BCG诱导和维持与术后BCG诱导和维持:基于一项纳入212例膀胱pT1尿路上皮癌伴或不伴CIS患者的研究,术后MMC-EMDA序贯BCG可能(证据质量低)导致复发时间延长(风险比(HR)0.51,95%CI 0.34至0.77;相当于每1000名参与者中少181例,95%CI少256例至少79例)和疾病进展时间延长(HR 0.36,95%CI 0.17至0.75;相当于每1000名参与者中少63例,95%CI少82例至少24例)。我们对MMC-EMDA对严重不良事件的影响不确定(证据质量非常低)(RR 1.02,95%CI 0.21至4.94)。4. 单剂量术前MMC-EMDA与单剂量术后MMC-PD:基于一项纳入236例原发性pTa和pT1尿路上皮癌患者的研究,术前MMC-EMDA可能(证据质量中等)导致复发时间延长(HR 0.47,95%CI 0.32至0.69;相当于每1000名参与者中少247例,95%CI少341例至少130例),中位随访时间为86个月。我们对MMC-EMDA对疾病进展时间的影响不确定(证据质量非常低)(HR 0.81,95%CI 0.00至259.93;相当于每1000名参与者中少34例,95%CI少193例至多807例)和严重不良事件的影响不确定(RR 0.79,95%CI 0.30至2.05)。5. 单剂量术前MMC-EMDA与单纯TURBT:基于一项纳入233例原发性pTa和pT1尿路上皮癌患者的研究,术前MMC-EMDA可能(证据质量中等)导致复发时间延长(HR 0.40,95%CI 0.28至0.57;相当于每1000名参与者中少304例,95%CI少390例至少198例),中位随访时间为86个月。我们对MMC-EMDA对疾病进展时间的影响不确定(证据质量非常低)(HR 0.74,95%CI 0.00至247.93;相当于每1000名参与者中少49例,95%CI少207例至多793例)或严重不良事件的影响不确定(HR 1.74,95%CI 0.52至5.77)。 作者结论:虽然使用EMDA灌注膀胱内MMC可能会使特定患者群体的复发时间延迟,但我们不确定其在所有情况下对严重不良事件的影响。降低证据质量评级的常见原因是研究局限性和不精确性。基于EMDA的MMC给药的潜在作用可能在于无法获得更成熟药物(如BCG)的情况下。在大多数比较的证据质量为低或非常低的情况下,我们对效应估计值的信心有限,真实效应大小可能与本文报道的有很大差异。
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