The management of patients with upper tract urothelial carcinoma (UTUC) is challenging due to the lack of high-level evidence, which results from the disease's overall rarity. The standard of care treatment for patients with high-risk disease (high-grade or invasive) is radical nephroureterectomy (RNU), with some advocating for the added use of neoadjuvant (NAC) or adjuvant platinum-based chemotherapy . The motivation to pursue NAC, as opposed to adjuvant, chemotherapy for patients with high-risk UTUC is based on several important observations. First, data from the treatment of high-risk bladder cancer indicate improved survival in patients who receive NAC chemotherapy. Second, most patients with high-risk UTUC suffer from underlying renal insufficiency, and significant loss of renal reserve occurs after nephrectomy. This loss precludes effective dosing and regimen of chemotherapy in the adjuvant setting, providing one of the most compelling reasons for pursuing the NAC approach. Third, data indicate that the survival rates of patients with UTUC have not improved in the past 2 decades, during a time when upfront RNU was considered the standard of care and advances in imaging and endoscopy presumably may have allowed earlier detection of disease.
In the NAC setting, six retrospective comparative studies investigated NAC in UTUC . Overall downstaging to pT0N0M0 was recorded in 11–28% of all stages UTUC treated with NAC. Retrospective experiences and subset analyses from modern prospective trials of NAC chemotherapy suggest that this approach is warranted. The largest retrospective experience reported on 267 patients treated with NAC and RNU between 2005 and 2017 . The overall rates of pathological complete response (CR) and pathological downstaging were 10.1 and 44.9%, respectively. On multivariable analysis, neither the type of chemotherapy (cisplatin-based or not) or the number of administrated cycles were statistically associated with pathological response. Pathological downstaging was the strongest prognostic factor for recurrence-free survival (RFS) (HR 0.2, P < 0.001), cancer specific survival (HR 0.19, P < 0.001), and overall survival (OS) (HR 0.40, P < 0.001). Recently, a multiinstitution prospective phase II trial was reported investigating pathologic CR (pCR) after NAC for high-grade UTUC . Patients planned for RNU were assigned to four NAC cycles of either accelerated methotrexate, vinblastine, doxorubicin, cisplatin (aMVAC) for baseline creatinine clearance (CrCl) more than 50 ml/min or gemcitabine and carboplatin (GCa) for 30 less than CrCl less than 50 ml/min. Accrual goal was 30 patients per arm. Eighteen percentage pCR was considered worthy of further study, whereas 4% pCR would not justify pursuit of this regimen. With 28 eligible patients per arm, success was defined as more than three pCRs (10.7%) in a given arm. Secondary endpoints included safety, renal function, and oncologic outcomes. From 2015 to 2017, 30 patients enrolled in the aMVAC arm. Six enrolled in the GCa arm, which closed for poor accrual. Of 29 eligible aMVAC patients, 80% completed all planned treatments, three achieved ypT0N0 (10.3%). Grade 3–4 toxicity rate was 23% in the aMVAC arm, with no grade 5 events. This phase 2 study supports aMVAC NAC administration in patients with high-grade UTUC and CrCl more than 50 ml/min.
In the adjuvant setting, the POUT trial, a phase 3 multicenter UK effort, enrolled 261 patients with locally advanced and/or node-positive UTUC (pT2-T4 and/or pN0-3 M0) between 2012 and 2017 . The patients were randomized (1 : 1) to four cycles of adjuvant gemcitabine-cisplatin (gem-cis)/gem-carboplatin (glomerular filtration rate 30–49 ml/min) or surveillance following RNU. Patients with a glomerular filtration rate less than 30 and those with incompletely resected macroscopic disease where excluded from the trial. Patients were followed closely with cross-sectional imaging and cystoscopy every 6 months for the first 2 years and transitioned to annual follow-up for a total of 5 years. The primary endpoint for the trial was disease-free survival (DFS), with RFS, OS, toxicity, and quality of life being secondary endpoints. The trial was expected to recruit 338 patients to detect a 15% improvement in 3-year DFS; however, the safety monitoring committee stopped the trial early due to significant improvement in observed DFS. Thus, the intention to treat analysis was conducted on 261 patients with 132 patients in the chemotherapy arm and 129 in the surveillance one. The majority of patients enrolled had pT3 disease (30% pT2, 65% pT3) and were node negative following lymph node dissection (91%). Noteworthy, of the patients receiving adjuvant chemotherapy, 66% were treated with gem-Cis, and 68% successfully completed the four-planed chemotherapy cycles. Approximately 50% of patients undergoing chemotherapy developed a grade 3 or greater adverse event with only one patient suffering a death related to an upper GI bleed.
The POUT trial met its primary endpoint: a significant improvement in DFS [HR 0.49 (confidence interval (CI) 0.31–0.76), P = 0.001] was observed at a median follow-up of 17.3 months. Following adjustment for nodal involvement the difference was more pronounced with an HR 0.47 (CI 0.30–0.74), P = 0.001. On univariable analyses, positive margins and receipt of gem-carboplatin were not associated with a an improved DFS following chemotherapy, which may be related to the short follow-up and to the low sample size, but still questioning the potential benefit of a noncisplatin (i.e., carboplatin) regimen. On secondary end-points, adjuvant chemotherapy was also associated with an improvement in RFS [HR 0.49 (CI 0.30–0.78), P = 0.02]. A difference in the OS curves favoring the adjuvant chemotherapy arm, but the difference remained nonsignificant likely due to the short follow-up.
In summary, the POUT trial provides exciting and convincing level I evidence on the benefit associated with adjuvant chemotherapy administration in patients with invasive or node-positive UTUC, therefore becoming the standard of care. The unanswered questions are the potential benefit of noncisplatin-based chemotherapy regimens (thus questioning the even more strong rationale for NAC chemotherapy in the setting of UTUC where the radical surgery inevitably affects renal function) , the consistency of the benefit among subgroups (pN0/pN+, positive margins,…) and the benefit of adjuvant chemotherapy over chemotherapy at the time of relapse. The latter is of importance, as in muscle-invasive bladder cancer, adjuvant chemotherapy failed to demonstrate a significant improvement in OS compared with delayed chemotherapy at the time of relapse, although lack of power, as a result of low accrual, might have impacted the outcomes . Finally, the immunotherapy revolution that is ongoing in UC will likely impact the management of patients with UTUC. To date, clinical trials are ongoing in the adjuvant setting of UC that are including UTUC patients, and in the NAC setting with pembrolizumab administration.
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