Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Department of Urology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Eur Urol. 2020 Sep;78(3):387-399. doi: 10.1016/j.eururo.2020.02.012. Epub 2020 Mar 4.
There is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR.
To elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results.
We performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis.
Median CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities.
We demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space.
In this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer.
对于卡介苗（BCG）无反应的非肌肉浸润性膀胱癌（NMIBC），迫切需要有效的膀胱保留疗法。由于目前缺乏可用作对照的有效药物，美国食品和药物管理局开始接受原位癌（CIS）患者的单臂试验，使用完全缓解率（CRR）和缓解持续时间作为主要终点来支持药物上市申请。尽管此后该领域的临床试验有所增加，但对于 CRR 的临床相关基准尚无共识。
阐明 BCG 失败后使用膀胱保留剂的 CRR 和无复发生存率（RFR），为未来的临床试验结果提供参考。
我们对利用膀胱内 BCG 治疗后复发的 NMIBC 进行了膀胱保留治疗的临床试验进行了系统评价（PROSPERO CRD42019130553）。检索了 MEDLINE、EMBASE 和 Cochrane 图书馆。从参考文献搜索和会议摘要中确定的相关研究也进行了检索，以补充系统评价。共有 42 项研究使用 24 种治疗方案，共 2254 名患者纳入最终分析。
治疗包含 CIS 肿瘤的患者在治疗后 6 个月的中位 CRR 为 26%，12 个月时为 17%，24 个月时为 8%。相比之下，仅在乳头状肿瘤研究中，6 个月时的中位 RFR 为 67%，12 个月时为 44%，24 个月时为 10%。具体在 BCG 无反应人群中，用分枝杆菌 phlei 细胞壁核酸复合物治疗包含 CIS 的患者的 6 个月和 12 个月 CRR 分别为 45%和 27%，而其他研究的中位 6 个月、12 个月和 24 个月无病生存率分别为 43%、35%和 18%。中位无进展率为 91%：包含 CIS 的研究为 95%，仅乳头状复发的研究为 89%。膀胱内药物的毒性通常较轻，极少数出现剂量限制毒性。
我们证明，迄今为止，膀胱保留疗法在 BCG 治疗后的 NMIBC 患者中取得了适度的疗效。本研究的结果将为 BCG 无反应空间中新兴试验结果提供参考。
在这项研究中，我们发现，在卡介苗（BCG）治疗后，膀胱保留疗法在非肌肉浸润性膀胱癌患者中取得了适度的疗效。这些结果将为用于治疗 BCG 无反应性膀胱癌的挽救性药物的未来临床试验结果提供信息。
