Context

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.

Objective

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.

Evidence acquisition

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.

Evidence synthesis

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.

Conclusions

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.

Patient summary

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.

中文翻译：

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膀胱内卡介苗治疗非肌肉浸润性膀胱癌后膀胱保留治疗的疗效的系统评价。

语境

对于卡介苗 (BCG) 无反应的非肌肉浸润性膀胱癌 (NMIBC)，迫切需要有效的保留膀胱疗法。由于目前缺乏可用作对照的有效药物，美国食品药品监督管理局开始接受针对原位癌（CIS）患者的单臂试验，采用完全缓解率（CRR）和缓解持续时间作为支持营销应用程序的主要端点。尽管该领域的临床试验随之增加，但对于 CRR 的临床相关基准尚未达成共识。

客观的

阐明 BCG 失败后使用保留膀胱药物的 CRR 和无复发率 (RFR)，以便为未来的临床试验结果提供参考框架。

取证

我们对使用保留膀胱疗法治疗膀胱内 BCG 后复发的 NMIBC 的临床试验进行了系统评价 (PROSPERO CRD42019130553)。检索是在 MEDLINE、EMBASE 和 Cochrane 图书馆中进行的。检索了从书目搜索和会议摘要中确定的相关研究，以补充系统评价。共有 42 项研究使用 24 种治疗方案，包括 2254 名患者，用于最终分析。

证据综合

治疗含 CIS 肿瘤的中位 CRR 在治疗后 6 个月为 26%，在 12 个月为 17%，在 24 个月为 8%。相比之下，仅乳头状研究的中位 RFR 在 6 个月时为 67%，在 12 个月时为 44%，在 24 个月时为 10%。特别是在 BCG 无反应人群中，接受草分枝杆菌细胞壁-核酸复合物治疗的含 CIS 患者的 6 个月和 12 个月 CRR分别为 45% 和 27%，中位数为 6、12 和 24 -mo 其他研究中的无病率分别为 43%、35% 和 18%。中位无进展率为 91%：在包含 CIS 的研究中为 95%，在仅限于乳头状复发的研究中为 89%。膀胱内给药的毒性通常是轻微的，剂量限制性毒性很少。

结论

我们证明，迄今为止，保留膀胱的疗法在 BCG 后的 NMIBC 患者中取得了适度的疗效。当前研究的结果将作为 BCG 无反应空间中新出现的试验结果的参考框架。

患者总结

在这项研究中，我们发现保留膀胱的疗法在卡介苗 (BCG) 后的非肌肉浸润性膀胱癌患者中取得了适度的疗效。这些结果将有助于为用于治疗 BCG 无反应性膀胱癌的补救剂的未来临床试验结果提供信息。