This past year, the New England AUA Sectional meeting hosted a live presentation of the AUA Upper Tract Urothelial Cancer (UTUC) course. This case-based review served to highlight key points and nuances in the modern management of UTUC. Herein, we provide a hopefully informative and engaging summary of the course’s content.

Once the urologist has made the diagnosis of UTUC, accurate risk stratification is key to the successful management of the disease. The course highlighted a number of predictive nomograms that can accurately preoperatively risk-stratify a patient’s disease. Indeed, investigators have designed several individual nomograms to predict the risks, respectively, of muscle-invasive UTUC, high-risk nonorgan confined disease, and postoperative disease recurrence.^1-3 These nomograms incorporate readily available information including patient characteristics, biometric data, the presence or absence of hydronephrosis, tumor characteristics, and clinical stage. Additional nomograms based mainly on post-nephroureterectomy pathology can predict long-term survival and disease recurrence with approximately 70%-80% accuracy.^4-7 Urologists may use these nomograms to inform decisions on the utility of adjunctive treatment strategies.

Low-risk, low-grade disease typically harbors a distinctly more indolent phenotype, so urologists should understand differences in the initial management of this disease state. Despite the nonaggressive nature of most low-grade tumors, most recent data from the National Cancer Database demonstrate that over 50% of patients with low-grade UTUC undergo radical nephroureterectomy, which likely represents gross overtreatment.⁸ In fact, with contemporary technological advances, most of these tumors are now amenable to renal-sparing management primarily by endoscopic thermal energy ablation and subsequently by surveillance with ad hoc intervention.⁹ Moreover, the advent of Food and Drug Administration–approved intracavitary mitomycin gel (JelMyto) has further augmented renal-sparing options in this space.^10,11 Indicated for both chemoablation of persistent disease up to 2 cm in size and prevention of recurrent disease, this treatment offers a 48% complete response rate at 1 year. Though complicated by ureteral stricture in 30%-40% of cases according to the OLYMPUS trial, such strictures may, in our expert opinion, resolve by means of conservative management with a combination of steroid taper, treatment holiday, and/or ureteral stenting.^10,11

Beyond the endoscopic treatment of low-risk disease, we reinforced current standards for surgical management for a range of disease presentations. It is noted that nephroureterectomy with bladder cuff endures as the gold standard for high-risk and high-grade localized UTUC. Meanwhile, distal ureterectomy with bladder cuff remains a reasonable option for distally located disease. Of note, level 1 evidence from 2 randomized trials supports the use of perioperative instillation of single-dose intravesical chemotherapy within 24 hours of open or minimally invasive intervention. This intervention prevents 50% of intravesical recurrences of urothelial carcinoma.^12,13 It continues, however, to be underutilized by urologists.¹⁴ At our institution, we utilize single-dose intravesical chemotherapy also after endoscopic ablation of UTUC. Though there are not direct data to support this practice, it is sensible that the preventive benefit would translate to the endoscopic setting, and the treatment is nonetheless with minimal risk.

Emphasis is further placed on the role and timing of systemic chemotherapy. Patients deemed high-risk should be considered for systemic therapy. High-level evidence via the POUT Trial supports the efficacy of adjuvant gemcitabine-platinum regimens¹⁵ while the ECOG-ACRIN 8141 study has demonstrated safety of neoadjuvant methotrexate-vinblastine-doxorubicin-cisplatin and suggests this as an effective treatment strategy with an approximately 15% complete response rate,¹⁶ though high-level evidence is still lacking. Given the available data, substantial consideration should be given to anticipated post-nephroureterectomy estimated glomerular filtration rate (eGFR), which may be roughly calculated through assessment of global and split renal function. High-risk patients with currently normal eGFR but anticipated postoperative eGFR <50 mL/min should be offered neoadjuvant chemotherapy. Despite level 1 evidence to support the practice, there is a high chance in this scenario that the patient will benefit from platinum-based chemotherapy but will be ineligible due to limitation by low eGFR. Conversely, patients with unclear risk and anticipated postoperative eGFR >50 mL/min should undergo up-front nephroureterectomy with bladder cuff; in this case, final pathology will aid in risk stratification, which will more accurately determine those who will most benefit from cisplatin-containing regimens.

A common treatment dilemma—the high-risk patient with low pre-treatment eGFR—necessitates alternative treatment regimens. Those patients whose eGFR remains >30 mL/min will be candidates for carboplatin-based regimens, which showed similar efficacy to cisplatin-based therapy in the POUT Trial.^9,15 Our institution is also involved in the ongoing ECOG 8192 clinical trial, which contains an arm investigating the activity of neoadjuvant gemcitabine-durvalumab in cisplatin-ineligible patients with UTUC.¹⁷ There is, furthermore, limited evidence to support use of gemcitabine-taxol-anthracycline–based regimens that is mainly rooted in a phase 2 study of low eGFR patients with advanced urothelial cancer of the bladder: 7/39 patients in this trial experienced complete responses to treatment and 15/39 experienced partial responses.^18,19 The dilemma also draws attention to the recent Food and Drug Administration approval of several immune-checkpoint inhibitors in the treatment of advanced urothelial cancer.^20-22 Most notably, nivolumab has been shown in the phase 3 Checkmate-274 study to have a modest benefit of 20.8 vs 10.8 months in disease-free survival as compared with placebo. We suggest that immunotherapy may pose a reasonable initial conservative treatment strategy in the unique dilemma of the high-risk patient with solitary kidney who would be rendered dialysis-dependent by local extirpative surgery.

In advanced disease states, including those with clinically positive nodes, we emphasize that chemotherapy as opposed to surgery should comprise the up-front, primary therapy. Though retrospective in nature, available data clearly demonstrate only an approximately 25% durable 5-year survival in pathologically node positive patients who underwent radical surgery with lymphadenectomy.^23,24 In light of these findings, it is important to consider that surgery is largely non-curative and may delay effective systemic treatment. A minimum of 6 cycles of chemotherapy is desired, and typically 2 additional cycles are given past maximal disease response. Urologists may later consider radical extirpative surgery as a consolidative measure if a favorable response to this primary treatment is observed.⁹

In all cases, it is important to remember that UTUC can represent a manifestation of Lynch syndrome and that the urologist may possess a unique opportunity to identify and thereby make a large impact on such patients. Lynch syndrome is a heritable condition that raises the risk of many malignancies—primarily colorectal, endometrial, gastric, and ovarian—due to a single-hit germline mutation of DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). Up to 5% of patients with UTUC harbor mutations for Lynch syndrome.^25,26 Urologists may screen for Lynch syndrome first by determining if the patient meets the Amsterdam criteria (“The 3-2-1 Rule:” (1) 3 successive generations with Lynch-related cancer, (2) 2 of whom are first-degree relatives, (3) 1 of whom was diagnosed before age 50) followed by evaluation of pathology specimens for immunohistochemical staining of mutant mismatch repair proteins and PCR for high microsatellite instability. Positive findings should prompt referral to a medical geneticist for germline testing. Confirmation of this diagnosis holds substantial implications, as afflicted patients and family members do significantly benefit from intensive, enhanced, multi-organ cancer screening schedules. Urologists should accordingly screen for associated personal and familial histories of relevant cancers and consider genetic testing in these patients.^25,26

We hope that all have found this article informative. The management of UTUC continues to exist in a dynamic treatment space with many recent and upcoming developments. We optimistically anticipate and advise attention toward advances in the treatment of this disease.