On April 15, 2020, the U.S. Food and Drug Administration (FDA) approved a unique mitomycin hydrogel formulation (Jelmyto®) for treatment of low grade (LG) upper tract urothelial carcinoma (UTUC). This was based on results of a single-arm, phase 3, international clinical trial.¹ The unique thermo-reversible hydrogel is in a viscous fluid state when chilled, but quickly becomes a semisolid gel at body temperature and subsequently dissolves in urine at a steady state, releasing mitomycin into the urine over 4 to 6 hours. The amount of Jelmyto instilled for the trial depended on the volume of each patient’s renal pelvis, which was assessed under fluoroscopy by the urologist. Results showed a 58% complete response in 71 patients with cytology-negative LG tumors of the renal pelvis measuring 0.5 to 1.5 cm above the ureteropelvic junction.¹ Patients presenting with larger tumors or tumors in the ureter could have debulking laser ablation to allow eligibility, and multiple tumors were allowed if they were otherwise size and location eligible. This outpatient, office-based treatment was given via cystoscopic placement of a 5Fr to 7Fr ureteral catheter with injection of the unique hydrogel chemotherapy combination into the renal pelvis/calyces once a week for 6 weeks, with ureteroscopic assessment for complete response performed 4 weeks later. Patients who had a complete response had the option of continuing monthly maintenance for up to 11 months. Updated durability results from this trial, which were presented at the 2020 winter meeting of the Society of Urologic Oncology, demonstrated 80% durability at 1 year and no apparent incremental benefit from maintenance therapy, although this was highly variable and given at the discretion of the principal investigators.

The approval of Jelmyto represents 2 major breakthroughs. From a clinical research perspective, it is the first sponsored drug trial for UTUC. The application to the FDA received Priority Review, Breakthrough Therapy, Fast Track and Orphan Drug designations, all of which expedited its approval. Although it has long been thought that such studies could not be accomplished for a rare disease such as UTUC, the pharmaceutical industry should now recognize that this is a space they can invest in with full urological support. It also puts our cooperative clinical trials groups on notice that transformative trials are possible for this rare disease. In fact, the United Kingdom has demonstrated that even relatively large randomized controlled studies can be accomplished for UTUC, and it has done so not once, but twice.^2,3

From a practical perspective, this establishes a new standard where one did not really exist if we agree that nephroureterectomy for LG low volume UTUC is mostly overtreatment, and that endoscopic management never satisfactorily addressed the high recurrence rates. Yet concerns regarding ureteral narrowing/strictures associated with Jelmyto, which occurred in 31% of cases, need to be addressed. These effects increased with number of doses delivered but appeared to be reversible in many cases. It is unclear how much was contributed by multiple manipulations or exposure to mitomycin. The effects are likely multifactorial: strictures have long been known to be associated with endourological management of UTUC,⁴ and mitomycin has also been reported to cause rare yet significant cases of chemical cystitis that may be driven by an eosinophilic response,⁵ so it is likely that these multiple insults are potentially additive.

Figure 1. Retrograde instillation of mitomycin hydrogel during office cystoscopy in patient with bifid renal pelvis and tumor in upper pole. After contrast injection, ureteral catheter is placed into upper pole system (A) and hydrogel injected while pulling back ureteral catheter in order to primarily treat upper pole (B), while remainder is delivered into lower pole. Hydrogel is radiolucent and seen as filling defect displacing contrast material.

Figure 2. Instillation of mitomycin hydrogel in patient with straightforward anatomy via nephrostomy tube (patient also has indwelling stent). For demonstration purposes, contrast material has first been injected into renal pelvis (A); radiolucent hydrogel is instilled immediately after, displacing most of contrast material (B).

Please note that the following description is off-label and based on empirical experience that has not been formally studied. In these cases, what I and other principal investigators have done is provide a treatment holiday, prescribe a Medrol® (methylprednisolone) Dosepak and delay subsequent treatments by 2 to 3 weeks, with a reassessment (either ultrasound or retrograde pyelogram) to ensure resolution before restarting treatment. I also frequently give steroids with each subsequent treatment in patients who experienced any narrowing. Some investigators have also left a stent and instilled the drug with the stent in place. One approach being considered by many urologists is placement of a nephrostomy tube (NT) for antegrade instillation in order to avoid the mechanical trauma of retrograde instillation. While there are no data to provide guidance on this approach, there is no contraindication either. Instillation via NT actually solves another practical dilemma for urologists who do not have fluoroscopy available in their office cystoscopy space: it can be performed much more simply in an office setting without the need for cystoscopy or fluoroscopy. However, initial placement of the tube will have to be done thoughtfully through an uninvolved calyx so as not to transgress tumor, and it may not be possible to direct the gel directly into the area of disease, such as in bifid or other complex anatomy (fig. 1). One advantage I find is that the hydrogel actually flows much faster and more evenly into the renal pelvis and calyces via the larger diameter, multi-orifice NT (fig. 2). Whether NT instillation will result in fewer strictures with equivalent efficacy remains to be seen.

One common question I have been asked is if this can be used as an adjuvant after complete laser ablation in order to prevent recurrences, with fewer doses delivered. While there are no available data on its efficacy purely as an adjuvant, this approach certainly makes sense given what we know so far, and it is a setting that I will also be considering in my practice. Another question is whether fewer instillations are effective; urologists will have to use some judgment here as, again, there are no data, but for a patient with very minimal disease, or for example highly multifocal yet small volume disease, or after complete endoscopic ablation, this may be a sensible approach in order to mitigate the stricture concern while addressing recurrence risk.

Jelmyto is undoubtedly a major breakthrough as the first approved treatment for LG UTUC, adding to the sparse armamentarium of treatment options for urologists and their patients. But let’s not let this major development be the last, and let’s continue supporting efforts to improve the care of our patients with this disease.