Sequential Endoluminal Chemotherapy for Non-Invasive High-Grade UTUC

Vignesh T. Packiam, MD, of Rutgers Cancer Institute, and Katie S. Murray, DO, MS, of NYU Langone Urology and Bellevue Hospital, weigh multiple recent studies that explore the efficacy of gemcitabine/docetaxel as a frontline therapy for upper tract urothelial carcinoma, highlighting its potential as an alternative to BCG amid supply shortages and its promising outcomes in preserving kidney function.

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Dr. Murray: You have had a few recent publications looking at gemcitabine/docetaxel as frontline therapy for upper tract disease. Can you tell me about those studies?

Dr. Packiam: The upper tract is very challenging to treat. Our instruments are very small, so biopsies are not always accurate, and it is difficult to completely resect or ablate tumors. In cases where we can remove all visible disease, some patients are candidates for topical therapy to avoid nephroureterectomy and spare their kidneys. Traditionally, we have used Bacillus Calmette-Guérin (BCG) in that setting, similar to its use inside the bladder.

Unfortunately, with the BCG shortage, we have had to find alternative therapies for both the bladder and the upper tract. Gemcitabine and docetaxel have recently shown a lot of promise, similar to BCG inside the bladder. Our studies are looking at the utility of gemcitabine/docetaxel in the upper tract.

Dr. Murray: Were you looking at high-grade patients in the upper tract or those with carcinoma in situ (CIS)? Since biopsy is difficult, grading and staging can be complicated. Can you describe the patient population in these studies?

Dr. Packiam: The first study we published was a single-arm cohort of patients treated with gemcitabine/docetaxel, involving 31 patients and 41 upper tract units. Some patients had bilateral disease. In that initial study, we focused on patients with high-grade disease; 90% had CIS, either by biopsy or presumed by isolated high-grade cytology. Ten percent had completely ablated papillary disease.

In the follow-up study comparing gemcitabine/docetaxel to BCG, we aimed to homogenize the cohort by focusing exclusively on presumed CIS. About 10% had biopsy-proven CIS, but most diagnoses were made by high-grade upper tract cytology.

Dr. Murray: What is the take-home message from the first study regarding the use of gemcitabine/docetaxel for CIS of the upper urinary tract? How does it compare to the second study with BCG?

Dr. Packiam: We were excited by the first study’s results, with a median follow-up of 2.5 years. The 2-year upper tract recurrence-free survival was 54%, and over 90% of patients avoided nephroureterectomy, successfully keeping their kidneys intact.

Dr. Murray: That is exciting for high-grade disease, having a nephroureterectomy-free survival rate of over 50% at 2 years. Can you discuss your second study comparing CIS alone against BCG?

Dr. Packiam: In the second study, we had a control cohort using BCG. This study included 65 upper tract units, with 31 receiving BCG and 34 receiving gemcitabine/docetaxel. The BCG shortage in 2019 and again now has impacted follow-up times. The median follow-up for BCG patients was over 7 years, while for gemcitabine/docetaxel it was about 2.5 years.

The 2-year recurrence-free survival was 61% for BCG and 54% for gemcitabine/docetaxel. The nephroureterectomy-free survival at 2 years was 89% for BCG and 100% for gemcitabine/docetaxel. Tolerance was similar between both groups, showing comparable effectiveness to BCG.

Dr. Murray: Given the current BCG shortage, it sounds like these findings expand our options and help avoid nephroureterectomy. If BCG were not a problem in the future, how would you decide between BCG and gemcitabine/docetaxel for upper tract disease?

Dr. Packiam: We do not have a clear way to predict response to either treatment. Availability of BCG will influence decisions.

In our second study, many patients were heavily pretreated; 80% had a history of CIS inside the bladder, and more than 80% had previously received intravesical therapy. Since CIS is a field defect disease, poor response to BCG in the bladder might indicate a similar response in the upper tract.

As more effective treatments for the bladder are developed, we may see fewer late recurrences in the upper tract, potentially influencing our treatment choices.

Dr. Murray: I tell my patients it is an exciting time to be involved in bladder cancer treatment with so many new options. It will be interesting to see how new bladder treatments impact upper tract incidence.

Is there anything else you would like to add about these studies or future directions for gemcitabine/docetaxel and other chemotherapies in the upper urinary tract?

Dr. Packiam: Yes, there are exciting future directions for this work. Gemcitabine/docetaxel is being increasingly studied in both the bladder and upper tract. The question is whether we can do something better or more effective.

These studies mainly focused on patients with CIS or completely ablated papillary disease. We have seen success with Jelmyto, reverse thermal mitomycin C, for papillary low-grade UTUC. Future research might explore combination regimens for high-grade disease as well.