Shepherd Andrew Rh, Shepherd Emily, Brook Nicholas R
Department of Urology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia, 5000.
School of Medicine, The University of Adelaide, Adelaide, Australia.
Cochrane Database Syst Rev. 2017 Mar 8;3(3):CD012112. doi: 10.1002/14651858.CD012112.pub2.
Despite local therapies, commonly transurethral resection (TUR) followed by adjuvant treatments, non-muscle-invasive bladder cancer (NMIBC) has a high rate of recurrence and progression. Intravesical Bacillus Calmette-Guérin (BCG) has been shown to reduce recurrence and progression in people with NMIBC following TUR, however many people do not respond to treatment, have recurrence shortly after, or cannot tolerate standard-dose therapy. The potential for synergistic antitumour activity of interferon (IFN)-alpha (α) and BCG provides some rationale for combination therapy for people who do not tolerate or respond to standard-dose BCG therapy.
To assess the effects of intravesically administered BCG plus IFN-α compared with BCG alone for treating non-muscle-invasive bladder cancer.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2016), MEDLINE (OvidSP) (1946 to 2016), Embase (OvidSP) (1974 to 2016), ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) as well as reference lists of retrieved articles and handsearched abstract proceedings of relevant conferences for the past three years. We applied no language restrictions. The date of last search of all databases was 25 August 2016.
We included randomised controlled trials (RCTs) and pseudo-randomised trials assessing intravesically administered BCG plus IFN-α versus BCG alone in adults of either gender with histologically confirmed Ta and T1 superficial bladder cancer, with or without carcinoma in situ, treated with TUR.
Two review authors independently assessed study eligibility, extracted data, and assessed the risk of bias of included studies. We used Review Manager 5 for data synthesis and employed the random-effects model for meta-analyses. For prespecified outcomes, where we were unable to derive time-to-event information (e.g. time-to-recurrence), we assessed dichotomous outcomes (e.g. recurrence) instead. We assessed the quality of the evidence for the main comparisons using the GRADE approach.
We included five RCTs involving a total of 1231 participants with NMIBC in this review. Due to poor reporting, the risk of bias in the included studies was often unclear. We assessed the studies under two main comparisons: intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs), and intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT). Intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs): We observed no clear difference between BCG plus IFN-α and BCG alone for recurrence (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.44 to 1.32; 4 RCTs; 925 participants; very low-quality evidence) or progression (average RR 0.26, 95% CI 0.04 to 1.87; 2 RCTs; 219 participants; low-quality evidence). The included RCTs did not report on the other primary outcome of this review, discontinuation of therapy due to adverse events. Regarding secondary outcomes, we observed no clear difference for disease-specific mortality (RR 0.38, 95% CI 0.05 to 3.05; 1 RCT; 99 participants; very low-quality evidence). Two RCTs reporting contradictory findings for adverse events could not be pooled due to variation in definitions. There were no data from the included RCTs on time-to-death or disease-specific quality of life. Intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT): We observed shorter time-to-recurrence for participants in the BCG alternating with IFN-α group compared with the BCG alone group (hazard ratio (HR) 2.86, 95% CI 1.98 to 4.13; 1 RCT; 205 participants; low-quality evidence), but no clear differences in time-to-progression (HR 2.39, 95% CI 0.92 to 6.21; 1 RCT; 205 participants; low-quality evidence) and discontinuation of therapy due to adverse events (RR 2.97, 95% CI 0.31 to 28.09; 1 RCT; 205 participants; low-quality evidence). Regarding secondary outcomes, there were no clear differences between the BCG alternating with IFN-α and BCG alone groups for disease-specific mortality (HR 2.74, 95% CI 0.73 to 10.28; 1 RCT; 205 participants; low-quality evidence), time-to-death (overall survival) (HR 1.00, 95% CI 0.68 to 1.47; 1 RCT; 205 participants; low-quality evidence), or systemic or local adverse events (RR 1.65, 95% CI 0.41 to 6.73; 1 RCT; 205 participants; low-quality evidence). There were no data on disease-specific quality of life.
AUTHORS' CONCLUSIONS: We found low- to very low-quality evidence suggesting no clear differences in recurrence or progression with BCG plus IFN-α compared with BCG alone for people with NMIBC; there was no information to determine the effect on discontinuation of therapy due to adverse events. Low-quality evidence suggests BCG alternating with IFN-α compared with BCG alone may increase time-to-recurrence, however low-quality evidence also suggests no clear differences for time-to-progression or discontinuation of therapy due to adverse events.Additional high-quality, adequately powered trials using standardised instillation regimens and doses of both BCG and IFN-α, reporting outcomes in subgroups stratified by patient and tumour characteristics, and on long-term outcomes related not only to recurrence but also to progression, discontinuation due to adverse events, and mortality may help to clarify the ideal treatment strategy and provide a more definitive result.
尽管采用了局部治疗方法，通常是经尿道切除术（TUR）并辅以辅助治疗，但非肌层浸润性膀胱癌（NMIBC）的复发率和进展率仍很高。膀胱内灌注卡介苗（BCG）已被证明可降低TUR术后NMIBC患者的复发率和进展率，然而，许多患者对治疗无反应，术后不久复发，或无法耐受标准剂量治疗。干扰素（IFN）-α与BCG的协同抗肿瘤活性为不耐受或对标准剂量BCG治疗无反应的患者进行联合治疗提供了一些理论依据。
评估膀胱内灌注BCG加IFN-α与单纯灌注BCG治疗非肌层浸润性膀胱癌的效果。
我们检索了Cochrane对照试验中心注册库（CENTRAL）（2016年第8期）、MEDLINE（OvidSP）（1946年至2016年）、Embase（OvidSP）（1974年至2016年）、ClinicalTrials.gov、世界卫生组织国际临床试验注册平台（WHO ICTRP）以及检索到的文章的参考文献列表，并对手检过去三年相关会议的摘要汇编进行了检索。我们未设语言限制。所有数据库的最后检索日期为2016年8月25日。
我们纳入了随机对照试验（RCT）和半随机试验，评估膀胱内灌注BCG加IFN-α与单纯灌注BCG对经组织学证实为Ta和T1期浅表性膀胱癌、有或无原位癌、接受TUR治疗的成年男女的疗效。
两名综述作者独立评估研究的入选资格、提取数据并评估纳入研究的偏倚风险。我们使用Review Manager 5进行数据合成，并采用随机效应模型进行荟萃分析。对于预先设定的结局，若无法获得事件发生时间信息（如复发时间），我们则评估二分结局（如复发）。我们使用GRADE方法评估主要比较的证据质量。
本综述纳入了5项RCT，共涉及1231例NMIBC患者。由于报告质量较差，纳入研究的偏倚风险往往不明确。我们在两个主要比较下评估了这些研究：膀胱内灌注BCG加IFN-α与单纯灌注BCG（4项RCT），以及膀胱内灌注BCG与IFN-α交替使用与单纯灌注BCG（1项RCT）。膀胱内灌注BCG加IFN-α与单纯灌注BCG（4项RCT）：我们观察到，BCG加IFN-α与单纯BCG在复发率（平均风险比（RR）0.76，95%置信区间（CI）0.44至1.32；4项RCT；925例患者；极低质量证据）或进展率（平均RR 0.26，95%CI 0.04至1.87；2项RCT；219例患者；低质量证据）方面无明显差异。纳入的RCT未报告本综述的另一个主要结局，即因不良事件而停止治疗的情况。关于次要结局，我们观察到疾病特异性死亡率无明显差异（RR 0.38，95%CI 0.05至3.05；1项RCT；99例患者；极低质量证据）。两项关于不良事件报告结果相互矛盾的RCT，由于定义不同，无法合并。纳入的RCT没有关于死亡时间或疾病特异性生活质量的数据。膀胱内灌注BCG与IFN-α交替使用与单纯灌注BCG（1项RCT）：我们观察到，与单纯BCG组相比，BCG与IFN-α交替使用组患者的复发时间更短（风险比（HR）2.86，95%CI 1.98至4.13；1项RCT；205例患者；低质量证据），但在进展时间（HR 2.39，95%CI 0.92至6.21；1项RCT；205例患者；低质量证据）和因不良事件而停止治疗方面无明显差异（RR 2.97，95%CI 0.31至28.09；1项RCT；205例患者；低质量证据）。关于次要结局，BCG与IFN-α交替使用组与单纯BCG组在疾病特异性死亡率（HR 2.74，95%CI 0.73至10.28；1项RCT；205例患者；低质量证据）、死亡时间（总生存期）（HR 1.00，95%CI 0.68至1.47；1项RCT；205例患者；低质量证据）或全身或局部不良事件方面无明显差异（RR 1.65，95%CI 0.41至6.73；1项RCT；205例患者；低质量证据）。没有关于疾病特异性生活质量的数据。
我们发现低质量至极低质量的证据表明，对于NMIBC患者，BCG加IFN-α与单纯BCG相比，在复发或进展方面无明显差异；没有信息可确定其对因不良事件而停止治疗的影响。低质量证据表明，与单纯BCG相比，BCG与IFN-α交替使用可能会延长复发时间，然而低质量证据也表明，在进展时间或因不良事件而停止治疗方面无明显差异。额外的高质量、有足够样本量的试验，采用标准化的灌注方案以及BCG和IFN-α的剂量，按患者和肿瘤特征分层报告亚组结局，以及报告不仅与复发相关，还与进展、因不良事件而停止治疗和死亡率相关的长期结局，可能有助于阐明理想的治疗策略并提供更明确的结果。
