Which treatments are being investigated for urothelial tumors of the renal pelvis and ureters?

Updated: Aug 07, 2020
  • Author: Kyle A Richards, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
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In future, endoscopic ablative procedures will be used more commonly for low-grade, low-stage disease and in patients in whom renal-sparing therapy is indicated.

New agents for topical instillation therapy of upper tract urothelial tumors are being developed.

New markers are being investigated for diagnosis, prognostication, and surveillance. Mini-array comparative hybridization-based tests, like those under new investigation for bladder cancer, may be helpful in the future. [76]

Makise et al identified Melanoma Associated Antigen A (MAGE-A) as a promising prognostic indicator, as well as a potential future immunotherapeutic target for UTUC. Expression of MAGE A was associated with higher histologic grade; concomitant carcinoma in situ; higher Ki -67 proliferation index; and infiltration of CD3-, CD8-, and CD45RO-positive lymphocytes .High MAGE-A expression was significantly associated with shorter metastasis-free survival after nephroureterectomy. [77]

UTUC tumors also demonstrate mismatch repair deficiency, which can be utilized for targeted immunotherapy. Castro et al demonstrated, through molecular profiling, the presence of the hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy in a patient with sporadic, high-grade urothelial carcinoma of the renal pelvis. MMR deficiency phenotype was confirmed by the absence of MSH2 and MSH6. Immunohistochemical staining for programmed cell death ligand-1 (PD-L1) revealed 2+ staining in 80% of cells. The patient had a complete remission with immunotherapy utilizing MEDI4736 and MEDI0680, demonstrating the potential of this therapy in selected patients. [78]

 Urothelial carcinoma is also susceptible to checkpoint inhibition. In a landmark paper, Alexandrov et al characterized the prevalence of somatic mutations across human cancer types. Leading the way with the highest mutational burden were melanoma and non–small cell lung cancer (both adenocarcinoma and squamous cell carcinoma), the tumor types for which checkpoint inhibition have proven the most efficacious to date, followed closely by urothelial carcinoma. [79]

The first studies evaluating checkpoint inhibitors in urothelial carcinoma of the bladder involved ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte–associated antigen. In a "window of opportunity" study, 12 patients with high-grade T1/2 urothelial carcinoma who received two doses of ipilimumab prior to radical cystectomy demonstrated measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. Increased freqency of those cells may be a biomarker that correlates with increased likelihood of clinical benefit. [80]

In a subsequent study (NCT01524991), the addition of ipilimumab to chemotherapy with gemcitabine and cisplatin led to increased levels of circulating CD4+ and CD8+ cells and induced a potentially more immunostimulatory environment. [81]

Updated safety and efficacy results were presented at the Genitourinary Cancers Symposium in January 2016. [82] In 36 evaluable patients, the overall response rate was 64%, with 5 patients (14%) achieving a pathologic complete response. A high rate of adverse events were noted, namely 72% grade 3/4 adverse events and autoimmune adverse events. The study did not meet its primary endpoint of improved 1-year overall survival (OS).

Use of the PD-1 inhibitor pembrolizumab (MK-3475) in a large, multi-arm phase I trial that included 33 patients with recurrent or metastatic PD-L1–positive urothelial carcinoma.resulted in an overall response rate of 28%. The median OS was reported as 12.7 months. Three patients achieved complete remission. [83]

Data have also emerged for atezolizumab. In the MPDL3280A trial, which accepted urothelial carcinoma patients irrespective of PDL-1 staining status, the overall response rate was 34%, with 87 total patients evaluable, but notably, the response rate was 50% in the 46 patients with immune clel 2/3 status, with nine complete responses. Azetolizumab has been granted a “breakthrough therapy designation “ based on those results. [84]

Another PD-1 inhibitor, nivolumab, is currently being studied in a phase II single-arm study in patients with platinum-refractory metastatic urothelial carcinoma. In the near future, checkpoint inhibitors could be combined for better results. The above studies on metastatic urothelial carcinoma could be extrapolated to UTUC in the future.

In the near future, personalized genetic profiling of primary or metastatic tumor cells may become readily available for routine clinical decision-making, potentially allowing for identification of patients who are likely to respond to systemic therapy . [85]

Staging is often inadequate with currently available imaging. Future approaches should include the capability to delineate invasive from superficial disease.


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