Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
Institute of Urology and Reproductive Health, Sechenov University, Moscow, Russia.
J Urol. 2020 Apr;203(4):690-698. doi: 10.1097/JU.0000000000000644. Epub 2019 Nov 8.
Data supporting neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma are scant. In this multi-institution, prospective, phase II trial we investigated pathological complete responses after neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma.
Patients with high grade upper tract urothelial carcinoma in whom nephroureterectomy was planned were assigned to 4 neoadjuvant chemotherapy cycles of accelerated methotrexate, vinblastine, doxorubicin and cisplatin in those with baseline creatinine clearance greater than 50 ml per minute or gemcitabine and carboplatin in those with creatinine clearance 30 to 50 ml per minute or less. The study primary end point was a pathological complete response (ypT0N0). The accrual goal was 30 patients per arm. An 18% pathological complete response was considered worth further study while a 4% pathological complete response would not have justified pursuing this regimen. With 28 eligible patients per arm success was defined as 3 or more pathological complete responses (10.7%) in a given arm. Secondary end points included safety, renal function and oncologic outcomes.
A total of 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm from 2015 to 2017. Six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Of the 29 patients eligible for accelerated methotrexate, vinblastine, doxorubicin and cisplatin, including 23 men and 6 women with a median age of 65 years (range 40 to 84), 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0 and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9-28.8). In 1 patient receiving accelerated methotrexate, vinblastine, doxorubicin and cisplatin nephroureterectomy was deferred due to grade 4 sepsis. The grade 3-4 toxicity rate was 23% in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm with no grade 5 event.
Accelerated methotrexate, vinblastine, doxorubicin and cisplatin neoadjuvant chemotherapy in patients with high grade upper tract urothelial carcinoma and creatinine clearance greater than 50 ml per minute was safe and demonstrated predefined activity with a 14% pathological complete response rate. Final pathological stage ypT1 or less in more than 60% of patients is encouraging. Together the results of this prospective trial support the use of neoadjuvant chemotherapy in eligible patients with high grade upper tract urothelial carcinoma.
支持高级别上尿路尿路上皮癌新辅助化疗的数据很少。在这项多机构、前瞻性、二期试验中，我们研究了高级别上尿路尿路上皮癌新辅助化疗后的病理完全缓解情况。
计划行肾输尿管切除术的高级别上尿路尿路上皮癌患者被分配接受 4 个周期的加速甲氨蝶呤、长春碱、多柔比星和顺铂治疗，如果基线肌酐清除率大于 50ml/分钟；或吉西他滨和卡铂治疗，如果肌酐清除率为 30-50ml/分钟或更低。研究的主要终点是病理完全缓解（ypT0N0）。入组目标为每个治疗组 30 例患者。18%的病理完全缓解被认为值得进一步研究，而 4%的病理完全缓解则没有证明这种方案是合理的。每个治疗组有 28 例符合条件的患者，成功定义为在特定治疗组中有 3 例或 3 例以上的病理完全缓解（10.7%）。次要终点包括安全性、肾功能和肿瘤学结果。
2015 年至 2017 年，共有 30 例患者在加速甲氨蝶呤、长春碱、多柔比星和顺铂组入组。由于入组人数少，吉西他滨和卡铂组入组 6 例后关闭。在 29 例符合加速甲氨蝶呤、长春碱、多柔比星和顺铂治疗条件的患者中，包括 23 名男性和 6 名女性，中位年龄为 65 岁（范围为 40-84 岁），80%的患者完成了所有计划的治疗，3 例（10.3%）达到了 ypT0N0，1 例达到了 ypT0Nx，病理完全缓解率为 13.8%（90%可信区间为 4.9-28.8）。1 例接受加速甲氨蝶呤、长春碱、多柔比星和顺铂治疗的患者因 4 级败血症而推迟了肾输尿管切除术。加速甲氨蝶呤、长春碱、多柔比星和顺铂组的 3-4 级毒性发生率为 23%，无 5 级事件。
对于肌酐清除率大于 50ml/分钟的高级别上尿路尿路上皮癌患者，加速甲氨蝶呤、长春碱、多柔比星和顺铂新辅助化疗是安全的，并显示出预先设定的活性，病理完全缓解率为 14%。超过 60%的患者最终病理分期为 ypT1 或更低，这令人鼓舞。这项前瞻性试验的结果共同支持在有资格的高级别上尿路尿路上皮癌患者中使用新辅助化疗。
