Karsh Lawrence, Shore Neal, Soloway Mark, Bhat Gajanan, Reddy Guru, Leu Szu-Yun, Witjes J Alfred
The Urology Center of Colorado, Denver, CO, USA.
Carolina Urologic Research Center, Myrtle Beach, SC, USA.
Bladder Cancer. 2018 Jul 30;4(3):293-301. doi: 10.3233/BLC-180166.
Guidelines recommend a single postoperative instillation of intravesical chemotherapy within 24 hours of transurethral resection of bladder tumors (TURBT) in patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC) to reduce recurrence risk.
To evaluate the 2-year recurrence rate (2-YRR) of bladder cancer in randomized patients with Ta, G1-G2 histology who receive TURBT plus apaziquone versus TURBT plus placebo.
Two nearly identical Phase 3, multinational, randomized, double-blind, placebo-controlled trials were conducted in patients with histologically confirmed Ta, G1-G2 NMIBC (Target Population) to evaluate the efficacy/safety of a single instillation of apaziquone post-TURBT. A single intravesical instillation of apaziquone (4 mg/40 mL) or placebo was administered within 6 hours post-TURBT. The primary and secondary efficacy endpoints were 2-YRR and time to recurrence (TTR) respectively.
Overall, 1614 patients were enrolled, including 1146 patients in the Target Population. Individually, the two studies did not meet statistical significance for 2-YRR (38.0% vs 44.6% ; 39.7% vs. 46.3%). Because apaziquone is rapidly metabolized in blood, a subgroup analysis was performed by time window of drug instillation post-TURBT. Patients who had drug instilled in the time window 60±30 minutes post-TURBT demonstrated 20.3% and 20.8% reduction in 2-YRR and 56% (HR = 0.44) and 45% (HR = 0.55) reduction in hazards for TTR in two studies respectively. Apaziquone was well tolerated with minimal toxicity.
Two identical Phase 3 studies supported the safety of apaziquone (4 mg/40 mL) administered as a single intravesical instillation post-TURBT and identified efficacy when instilled within 60±30-minutes time interval which requires further study.
指南建议，对于低危和中危非肌层浸润性膀胱癌（NMIBC）患者，在经尿道膀胱肿瘤切除术（TURBT）后24小时内进行单次膀胱内化疗灌注，以降低复发风险。
评估接受TURBT加阿帕唑醌与TURBT加安慰剂的Ta期、G1 - G2组织学的随机分组患者的膀胱癌2年复发率（2 - YRR）。
针对组织学确诊为Ta期、G1 - G2 NMIBC的患者（目标人群）开展了两项几乎相同的3期、多国、随机、双盲、安慰剂对照试验，以评估TURBT后单次灌注阿帕唑醌的疗效/安全性。在TURBT后6小时内进行单次膀胱内灌注阿帕唑醌（4 mg/40 mL）或安慰剂。主要和次要疗效终点分别为2 - YRR和复发时间（TTR）。
总体而言，共纳入1614例患者，其中目标人群有1146例。两项研究单独来看，2 - YRR均未达到统计学显著性（38.0%对44.6%；39.7%对46.3%）。由于阿帕唑醌在血液中快速代谢，因此按TURBT后药物灌注的时间窗进行了亚组分析。在TURBT后60±30分钟时间窗内接受药物灌注的患者，两项研究中2 - YRR分别降低了20.3%和20.8%，TTR风险分别降低了56%（HR = 0.44）和45%（HR = 0.55）。阿帕唑醌耐受性良好，毒性极小。
两项相同的3期研究支持了TURBT后单次膀胱内灌注阿帕唑醌（4 mg/40 mL）的安全性，并确定了在60±30分钟时间间隔内灌注时的疗效，这需要进一步研究。
