Abstract
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The study was designed as a phase 2a trial. The primary endpoints of the study were safety and feasibility (>95% patients tolerated mitomycin [MMC] with no related adverse events reported). The secondary endpoint was recurrence free survival (RFS). Therefore, the immediate instillation of single dose of mitomycin (SDM) was proposed preoperatively to all patients with a diagnosis of papillary upper tract urothelial carcinoma (UTUC). All those patients who were not eligible to MMC (see M&M section of the article) or did not sign an informed consent were used as control series. To reduce the potential confounding factors, the patients subjected weekly to upper tract urothelial instillation were excluded from both groups (five patients in the SDM group and three patients in the control group). The populations (group A and group B) were compared (supplementary table S1) and were found similar in terms of UTUC characteristics [high-risk UTUC 10/17 (59%) vs 10/18 (56%) in groups A and B, respectively]. We agree with Okekeand colleagues that a selection bias is identified; however, even with the inclusion of those eight patients, a relative reduction of 33% [7/22 (31.8%) vs 10/21 (47.6%)] of urothelial recurrences was observed in the MMC group. Unfortunately the small series limits these results. Despite this, we believe that given the little data on this matter present in the literature, our results add value in the research of adjuvant alternative to the conservative management of UTUC.
Several concerns are also related to the potential histologic heterogeneity between upper urinary tract and bladder, as emphasized in the editorial comment by Okeke et al. 2 Normally, the number of cell layers in the upper urinary tract varies by location, with the renal pelvis having a slightly thinner urothelial layer than the ureter. 3 Other than that, UTUC lesions are histologically similar to urothelial bladder cancer, but the relative thinness of the muscle layer of the renal pelvis and ureter makes invasion through the muscle coat an earlier event. Furthermore, urothelial carcinomas are inherently multifocal and have a high propensity for recurrence after initial ablative treatment. These characteristics create challenging clinical scenarios, including multiple synchronous and/or metachronous tumors in different areas of the urothelium (upper urinary tract, bladder, and urethra). It is difficult to determine whether these lesions represent seeding sites of shedding tumor cells that originated from the same primary tumor or whether these are true second primary de novo lesions. In addition, according to the monoclonality hypothesis, exfoliated tumor cells are spread intraluminal to other parts of the urothelium. Most likely, both mechanisms may be present simultaneously. 4 These several differences might result in different chemotherapy response and, consequently, oncologic outcomes.
Finally, how to perform chemotherapy agent delivery is clearly a challenge. Recently, the U.S. Food and Drug Administration approved mitomycin gel (JELMYTO, UroGen Pharma) use for patients with low-grade UTUC. The efficacy determination was based on OLYMPUS (NCT02793128), an ongoing single-arm multicenter trial, enrolling patients with treatment-naive or recurrent low-grade noninvasive UTUC. This is certainly among the most appealing and promising ways to deliver the drug and opens doors to future prospective and possible randomized studies on this matter.