Greenberg Bladder Cancer Institute clinicians and scientists are pioneering innovative treatments to manage this rare, complex disease.
Topical Therapy for Low-Grade UTUC: Hydrogel Helps Save the Kidney
One of the challenges of treating low-grade UTUC is its location: the ureter, the tube that conveys urine from each kidney to the bladder, is very narrow; about 4 mm or less in diameter.
“The small size of the ureter has prevented adequate treatment with current technologies – until now,” says urologist Phillip Pierorazio, M.D. A novel hydrogel may be the game-changer doctors and patients have been waiting for. “This hydrogel is liquid when cooled, but it solidifies as it warms to body temperature. It can be infused with chemotherapy and delivered into the kidney to treat UTUC topically.”
The chemotherapy used in this case is Mitomycin C, a proven performer in bladder cancer, Pierorazio adds. “It’s very effective at killing urothelial cancers, and works great in the bladder.” The hydrogel is essential in getting – and keeping – the drug in place. “Before this drug became available, we had no means to get chemotherapy to stay in the kidney. Normal urine flow would wash it out before the drug could kill the cancer.”
The hydrogel, called Jelmyto, takes six hours to dissolve and release chemotherapy after it solidifies in the kidney. Pierorazio and colleagues at Hopkins were investigators in the first clinical trial using Mitomycin C for patients with low-grade UTUC. The trial’s results, published in Lancet Oncology, found no evidence of cancer one year after treatment in 60 percent of patients.
While up to 40 percent of patients experienced an inflammatory narrowing of the ureter, for nearly all of them, these symptoms were transient, and almost all patients were able to preserve their kidney. ““This is a major paradigm shift for patients with low-grade UTUC,” says Nirmish Singla, M.D., M.Sc., Director of Translational Research in Genitourinary Oncology and Co-Director of the UTUC multidisciplinary clinic. "Previously, all we had to offer were ineffective technologies or radical surgery. Now we have a topical therapy, and we expect more therapies to emerge in the coming years.” Hopkins is also a site for the ENLIGHTENED study, which will investigate a laser-based photodynamic therapy to ablate UTUC in the renal pelvis.
Multidisciplinary Clinic for Patients with UTUC
For more than 130 years, Johns Hopkins has provided expertise in treating difficult and rare diseases that doctors at some hospitals might never even come across: diseases like UTUC.
“UTUC is a rare and challenging cancer to manage, accounting for only 5 to 10 percent of all urothelial tumors,” says Nirmish Singla, M.D., M.Sc., “Treatment approaches have traditionally been extrapolated from bladder cancer, but mounting evidence suggests that UTUC and bladder cancers are actually disparate entities.”
For example: tobacco exposure is the most common risk factor for developing either UTUC or bladder cancer, but UTUC also has other risk factors, including Lynch syndrome (an inherited condition that raises the risk of many types of cancer) and exposure to aristolochic acid (found in some Chinese herbal medicines and also sold as weight-loss aids).
Furthermore, Singla continues, “UTUC is inherently subject to diagnostic and staging challenges, including both the technical challenges of biopsying tumors in the upper urinary tract and the limitations of conventional cross-sectional imaging.
The gold standard approach to surgically treating UTUC, radical nephroureterectomy (removal of the renal pelvis, kidney, ureter, and bladder cuff), is not without consequences, either, as it places patients at risk of chronic kidney disease.” Given the rarity of UTUC and the complexities of its management, very few centers nationwide have expertise in caring for patients with UTUC.
Recent clinical trials have shown a benefit to integrating systemic therapy with surgery in treating high-risk UTUC. “Thus, access to a multidisciplinary care team that includes an experienced urologic surgeon and genitourinary medical oncologist is paramount to optimizing outcomes in patients with UTUC,” says medical oncologist Jean Hoffman-Censits, M.D., Co-Director of the Women’s Bladder Cancer Program at the Sidney Kimmel Cancer Center.
Recognizing this critical need, as of June 2021, Johns Hopkins offers such a team, co-directed by Hoffman-Censits and Singla. The Clinic, held twice per month, offers streamlined, “one-stop,” personalized care from multiple specialists for patients with this rare and complex disease. Patients will also be able to take part in clinical trials andresearch studies. The clinic will be expanding to include specialists from other disciplines, including nephrology and genetics.
Same Patient, Different Types of Bladder Cancer
Some patients with cancer in one part of the bladder develop cancer in another part – and these cancers may be made up of different cells, have different biomarkers, and may require different treatment.
“Upper tract and lower tract bladder cancers often arise in the same patients, but the biological relationships between them are not clear,” says David McConkey, Ph.D., the Erwin and Stephanie Greenberg Professor of Urology and Director of the Greenberg Bladder Cancer Institute.
Recently, McConkey and colleagues performed RNA sequencing on upper tract urothelial carcinoma (UTUC) and bladder cancers and examined the tumors’ biological properties. “We found that the tumors could be grouped into two subsets: one that was enriched with biomarkers characteristic of bladder cancer luminal subtypes, and the other that was enriched with basal-like biomarkers. Interestingly, most of the bladder-then-upper tract cancers were concentrated in the basal-like subset, whereas most of the other cancers were luminal, and the basal-like cancers were associated with increased invasion and shorter disease-specific survival.”
“In addition, as is being appreciated in patients with lower-tract cancers, patients with UTUC basal-like cancers may benefit more from immunotherapy, whereas patients with luminal cancers might benefit more from targeted therapies, such as FGFR inhibitors (drugs that slow cell growth) or antibody-drug conjugates.” This work was published in the Journal of Urology.