Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; Department of Urology, La Croix du Sud Hospital, Institut Universitaire du Cancer Toulouse-Oncopole, Toulose, France.
Department of Urology, Spedali Civili of Brescia, Brescia, Italy; Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland.
Clin Genitourin Cancer. 2022 Aug;20(4):389.e1-389.e7. doi: 10.1016/j.clgc.2022.03.007. Epub 2022 Mar 10.
The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC.
We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation.
Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points.
Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.
唯一一项评估根治性肾输尿管切除术（RNU）后辅助化疗在上尿路尿路上皮癌（UTUC）中的作用的 III 期临床试验提前终止。因此，按照 Prentice 的说法，在此情况下不能评估最终的总生存（OS）替代终点。我们旨在确定一种可以作为 RNU 治疗 UTUC 后 OS 替代终点的中间临床终点（ICE）。
我们回顾性分析了 823 例在 8 家三级转诊中心接受 RNU 治疗的高级别 UTUC 患者。我们通过时间变化的 Cox 回归分析，探索任何复发（aR），定义为尿路或切缘部位的复发，以及远处转移（DM），定义为尿路和区域淋巴结以外的转移性疾病，对 OS 的作用，在 RNU 后 1、2、3 和 4 年的标志点进行拟合。通过内部验证，使用 Harrell 的 c 指数评估模型的判别能力。
幸存者的中位随访时间为 5.6 年（四分位距：2.0-8.8）。总体而言，391 例和 212 例患者分别发生了 aR 和 DM。在时间变化模型中，aR 和 DM 是 OS 的预测因素：风险比[HR]：1.20，95%置信区间[CI]：1.13-1.28（P<0.001）和 HR：1.26，95%CI：1.18-1.34（P<0.001）。RNU 后 3 年内进展为 DM 是预测 OS 的最有信息的 ICE（c 指数：0.81；HR：4.40；95%CI：2.45-7.92；P<0.001），与 1、2 和 4 年内进展为 DM 相比（c 指数分别为 0.74、0.76 和 0.78）。与任何标志点的任何复发相比，RNU 后 3 年内进展为 DM 也被发现对 OS 预测更优。
RNU 后 3 年内进展为 DM 是手术治疗 UTUC 的潜在 OS 替代终点。这一信息有助于患者咨询、未来研究设计，并加快正在进行的随机对照试验的结果发布。
