European Urology

In this month's edition of European Urology, Chromecki and coworkers report on a retrospective series of 2492 patients, pooled from 16 centers, who underwent nephroureterectomy (NU) for the treatment of upper tract urothelial carcinoma (UTUC) [1]. A multivariate analysis of patients with organ-confined UTUC treated by NU showed cancer-specific mortality and progression-free survival to be significantly influenced by age, pathologic stage, lymphovascular invasion, and tumor multifocality. We applaud the authors because this study is the largest of its kind to identify risk factors for UTUC progression and cancer-specific mortality.

This information improves our ability to risk-stratify patients with UTUC. In a similar study of 656 patients, Ouzzane et al. [2] identified age, pathologic stage, lymph node metastasis, tumor location, and tumor multifocality as predictors of cancer-specific mortality. Combined, these findings aid in discussions of disease prognosis and may guide management decisions. Despite these advances in our ability to identify patients most at risk of metastasis from UTUC, few strides have been made in the last 30 yr toward improving patient survival. How might we improve our ability to diagnose and manage patients with UTUC beyond the technical improvements of ureteroscopy and laparoscopy?

One important area of improvement has been the use of renal preservation techniques for those with low-grade Ta UTUC. In recent years, ureteroscopic instruments have seen significant improvements, allowing for successful diagnosis and, in selected cases, treatment of UTUC. Current guidelines support the local management of small, unifocal, low-grade Ta tumors, without evidence of invasion on computed tomography (CT) [3]. The latter criteria are required to avoid understaging. Such patients managed endoscopically have similar rates of cancer-specific and overall survival as compared to those undergoing NU [4] and [5]. However, there are limitations to this approach. For example, ureteroscopic biopsies are limited in their ability to accurately stage these tumors, with staging error up to 30% at the time of NU [6]. Furthermore, conservative management requires strict patient compliance, which may be problematic for some.

There has been little progress for patients with high-grade UTUC. Improving survival in high-risk patients requires the use of effective systemic chemotherapy or, alternatively, diagnosing patients prior to invasion. This would entail screening individuals at high risk of developing UTUC. The story is not dissimilar to that of urothelial cancer of the bladder, for which we use organ preservation effectively for low-grade urothelial cancers but have reached a plateau in terms of prognosis of invasive tumors.

Perioperative chemotherapy should be considered for patients with high-grade invasive UTUC. Our understanding of chemotherapy for UTUC is based on our experience with bladder cancer, as it is difficult to accrue similar information in patients with UTUC because of its low incidence. Several randomized prospective trials in patients with locally advanced bladder cancer have demonstrated a survival advantage with the use of induction or neoadjuvant cisplatin-based combination chemotherapy. Specifically, the long-term results of the BA06 30894 trial recently demonstrated a 16% reduction in the risk of death among patients with muscle-invasive urothelial cancer of the bladder treated with cisplatin, methotrexate, and vinblastine prior to cystectomy and/or radiotherapy [7].

The data on the use of adjuvant chemotherapy are less convincing [8]. As such, current guidelines fail to recommend this management strategy [3]. Moreover, following NU, patients experience a sharp decline in renal function, leaving only 19% eligible for cisplatin-based adjuvant chemotherapy [9]. Based on the assumption that tumors of the upper tract behave similarly to bladder tumors, experts now propose the use of neoadjuvant chemotherapy prior to NU for patients at high risk for invasion or metastasis [3]. Although early data have suggested that, when applied to UTUC, neoadjuvant chemotherapy may lead to significant tumor downstaging in patients proceeding to NU [10], no prospective long-term data are currently available.

Most important in a strategy to improve disease-free survival in patients with high-risk UTUC is development of a program to identify these tumors earlier (ie, a screening or early detection program). Guidelines from the European Association of Urology on the surveillance of both upper- and lower-tract tumors are outlined in Table 1. For patients with bladder cancer at high risk for recurrence and progression in the bladder, surveillance is recommended every 3 mo with flexible cystoscopy and cytology [11]. If we propose to “screen” those at high risk of developing UTUC (eg, those who have had a high-grade bladder cancer), we first have some obstacles to overcome. Unfortunately, for UTUC, we are limited in our ability to perform frequent surveillance with ureteroscopy. Current surveillance regimens, including CT urogram or renal ultrasound, have been unable to identify tumors in a timely fashion [12]. This may be due to the recommended 6- to 12-mo imaging interval, which is simply too infrequent [13]. More frequent imaging by CT scans has radiation risk and cost and is not practical, given the relatively low risk of developing such a tumor. However, let us propose consideration of a much more practical program: Because cytology is accurate for identifying high-grade urothelial cancer, obtain urine for cytology every 3 mo, possibly in addition to renal ultrasonography. A CT urogram could still be performed annually. Earlier identification of upper-tract tumors might allow for intervention at a point when we can still influence outcomes.

While we commend the work of Chromecki et al. [1], which undoubtedly will aid urologists in identifying those most at risk of UTUC progression following NU, we are reminded of where we fall short in our management of bladder cancer and UTUC. For more common cancers such as prostate, breast, cervix, and colon cancer, we have established screening protocols for those at high risk to diagnose and treat at earlier stages. However, we lack effective early detection protocols for patients at high risk for bladder cancer or UTUC. In terms of UTUC, patients with a history of high-grade bladder cancer or prior UTUC are at higher risk and should be considered for more frequent screening. Patients at a high risk for bladder cancer (eg, cigarette smoking history, occupational exposure, aged >60 yr) might be screened with annual cytology. Accurate prognostic factors will identify high-risk patients who would benefit from closer surveillance. To improve patient survival, the next step forward is to develop a better screening protocol.

Conflicts of interest

The authors have nothing to disclose.