临床 T2-4N0M0 期尿路上皮膀胱癌患者新辅助化疗和根治性膀胱切除术后 1 年无复发生存的建模：Ⅱ期临床试验终点。
Modeling 1-year Relapse-free Survival After Neoadjuvant Chemotherapy and Radical Cystectomy in Patients with Clinical T2-4N0M0 Urothelial Bladder Carcinoma: Endpoints for Phase 2 Trials.
机构信息
Vita-Salute San Raffaele University and Department of Urology, IRCCS San Raffaele Hospital, Milan, Italy.
Vita-Salute San Raffaele University and Department of Urology, IRCCS San Raffaele Hospital, Milan, Italy.
出版信息
Eur Urol Oncol. 2019 May;2(3):248-256. doi: 10.1016/j.euo.2018.08.009. Epub 2018 Sep 7.
BACKGROUND
Several ongoing phase 2 trials are evaluating new neoadjuvant therapy regimens in patients with muscle-invasive bladder cancer (MIBC). The 1-yr recurrence-free survival (RFS) after radical cystectomy (RC), with or without perioperative chemotherapy, can be used to model statistical assumptions and interpret outcomes from these studies.
OBJECTIVE
To provide a benchmark for predicting 1-yr RFS in patients with cT2-4N0 MIBC.
DESIGN, SETTING, AND PARTICIPANTS: We identified 950 patients with clinical stage T2-4N0 MIBC undergoing RC at 27 centers between 1990 and 2016. We assessed 1-yr RFS rates for patients managed with no perioperative chemotherapy, neoadjuvant chemotherapy (NAC), adjuvant chemotherapy (AC), or NAC followed by AC. Cox regression analyses tested for 1-yr postsurgical RFS predictors. A Cox-based nomogram was developed to estimate 1-yr RFS and its accuracy was assessed in terms of Harrell's c-index, a calibration plot, and decision curve analysis. We report 1-yr RFS rates across the nomogram tertiles.
RESULTS AND LIMITATIONS
The 1-yr RFS rates were 67.9% (95% confidence interval [CI] 64-72) after no perioperative chemotherapy, 76.9% (95% CI 72-83%) after NAC, 77.8% (95% CI 71-85%) after AC, and 57% (95% CI 37-87) after NAC+AC. On multivariable analysis, positive surgical margins (p=0.002), pT stage (p<0.0001), and pN stage (p<.0001) were significantly associated with RFS, while NAC was not (p=0.6). The model including all these factors yielded a c-index of 0.76 (95% CI 0.72-0.79), good calibration, and a high net benefit. The 1-yr RFS rates across nomogram tertiles were 90.5% (95% CI 87-94%), 73.4% (95% CI 68-79%), and 51.1% (95% CI 45-58%), respectively. The results lack external validation.
CONCLUSIONS
Benchmark 1-yr RFS estimates for phase 2 design of new neoadjuvant trials are proposed and can be used for statistical assumptions, pending external validation.
PATIENT SUMMARY
Our prognostic model predicting 1-yr survival free from recurrence of bladder cancer after radical cystectomy, with or without standard chemotherapy, could provide an improvement to the quality of phase 2 clinical trial designs and interpretation of their results.
背景
几项正在进行的 2 期临床试验正在评估新的新辅助治疗方案在肌层浸润性膀胱癌（MIBC）患者中的应用。根治性膀胱切除术（RC）后 1 年无复发生存率（RFS），无论是否有围手术期化疗，都可用于对这些研究的统计假设进行建模并解释结果。
目的
为预测 cT2-4N0 MIBC 患者的 1 年 RFS 提供基准。
设计、设置和参与者：我们在 1990 年至 2016 年间在 27 个中心识别了 950 例接受 RC 治疗的临床分期为 T2-4N0 MIBC 患者。我们评估了未接受围手术期化疗、新辅助化疗（NAC）、辅助化疗（AC）或 NAC 后 AC 治疗的患者的 1 年 RFS 率。Cox 回归分析测试了术后 1 年 RFS 的预测因素。开发了基于 Cox 的列线图来估计 1 年 RFS，并用 Harrell 的 c 指数、校准图和决策曲线分析来评估其准确性。我们报告了列线图三分位组的 1 年 RFS 率。
结果和局限性
无围手术期化疗后 1 年 RFS 率为 67.9%（95%置信区间 [CI] 64-72），NAC 后为 76.9%（95% CI 72-83%），AC 后为 77.8%（95% CI 71-85%），NAC+AC 后为 57%（95% CI 37-87）。多变量分析显示，手术切缘阳性（p=0.002）、pT 分期（p<0.0001）和 pN 分期（p<.0001）与 RFS 显著相关，而 NAC 则无显著相关性（p=0.6）。包括所有这些因素的模型产生了 0.76（95% CI 0.72-0.79）的 c 指数，良好的校准和较高的净收益。列线图三分位组的 1 年 RFS 率分别为 90.5%（95% CI 87-94%）、73.4%（95% CI 68-79%）和 51.1%（95% CI 45-58%）。结果缺乏外部验证。
结论
提出了用于新辅助试验 2 期设计的基准 1 年 RFS 估计值，可用于统计假设，等待外部验证。
患者总结
我们预测 RC 后 1 年无膀胱癌复发生存的预后模型，无论是否有标准化疗，都可以提高 2 期临床试验设计的质量，并解释其结果。
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