Upper Tract Urothelial Carcinoma – A Patient Population That Deserves More Attention in Clinical Trials

The majority of urothelial carcinomas occur in the lower urinary tract, yet 5-10% originate in the upper urinary tract, including the renal calyces, renal pelvis, and ureters.1  Although upper and lower urinary tract urothelial carcinoma may share similar histology, the natural history differs, and upper tract disease often has a higher incidence of local invasion at diagnosis.2  Risk factors for upper tract urothelial carcinoma are similar to those of the lower tract, but there are some unique risk factors are associated with environmental exposures.  For example, Taiwan has an extremely high incidence of upper tract urothelial carcinoma, with a counterintuitive 1:2 male-to-female ratio due to arsenic-contaminated water, termed Blackfoot disease.  Additionally, in both Taiwan and the Balkan countries, exposure to the Aristolochic herbs (fangchi and clematis) is carcinogenic, leading to progressive renal fibrosis and upper tract urothelial carcinoma.4, 5

Upper tract urothelial carcinoma biology is commonly linked with Lynch syndrome, an autosomal dominant disorder in impaired DNA mismatch repair that results in a high risk of colon, endometrial, ovarian, gastric, and upper tract urothelial carcinoma.6  However, Lynch syndrome is not a common event, with estimates of the entire population ranging between 1:2000 to 1:660.7  For most practicing clinicians, it is rare to encounter a patient with Lynch syndrome and upper tract urothelial carcinoma.  However, somatic fibroblast growth factor 3 (FGFR3) mutations are quite common, and whole exome sequencing on DNA and RNA has shown FGFR3 to be the most commonly mutated gene.8  Interestingly, upper tract urothelial carcinoma FGFR3 mutation incidence was found to be 74%.  Surprisingly, it was even higher in low-grade disease (92%) than high-grade disease (60%).

Upper tract urothelial carcinoma presents some unique challenges for urologic surgical management.  Intravesical administration of bacillus Calmette-Guerin (BCG) and mitomycin C is commonly used for risk reduction of recurrence and progression of carcinoma in situ and non-muscle invasive bladder cancer, however, the clinical effectiveness and modality of administration are controversial for upper tract disease.  Topical therapy for upper tract urothelial carcinoma can be administered through various approaches: 1) Directly into the bladder, hoping for vesicoureteral reflux via an indwelling ureteric stent, 2) Retrograde perfusion via an open-ended ureteric catheter, or 3) Anterograde perfusion via a percutaneous nephrostomy tube.  Another challenge for urologists is that approximately 50% of patients with upper tract urothelial carcinoma will develop lower tract disease, many cases of which are presumed to be through intraluminal distal seeding. 

For purposes of this article, we will focus more on systemic therapy clinical trials.  The first situation is neoadjuvant therapy, where general logic supports its utilization for upper tract disease, extrapolating from supportive data from bladder urothelial carcinoma.  This is due to the pragmatic advantage of having twice as many nephrons prior to surgical resection, as compared to adjuvant therapy post radical nephroureterectomy.  Since cisplatin-combination chemotherapy is typically administered, and the nephrotoxic side effects are well known, neoadjuvant therapy seems a preferred option when possible.  ECOG-ACRIN 8141 was a phase 2 open-label trial that treated patients with gemcitabine/cisplatin, resulting in a 14% complete response rate.9  Similarly, another multicenter trial also treated patients with neoadjuvant gemcitabine/cisplatin, resulting in a pathologic downstaging response rate of 60%, defined as <pT1N0.10  The 2-year progression-free survival rate was quite respectable at 76%.  Other chemotherapy, molecular targeted therapy, and combination immunotherapy neoadjuvant trials are highlighted below.

The adjuvant POUT trial, a multicenter randomized controlled trial from the United Kingdom, provides the strongest data supporting peri-operative chemotherapy for upper tract urothelial carcinoma.  This trial enrolled 261 patients with upper tract disease who was status post radical nephroureterectomy staged as either pT2-4N0-3M0 or pTanyN1-3M0, randomizing this patient population to adjuvant chemotherapy vs. surveillance.  Specifically, disease-free survival after adjuvant gemcitabine/cisplatin or gemcitabine/carboplatin was improved over surveillance, with a HR 0.45, 95% CI 0.30-0.68, p=0.0001.11  Three-year event free survival estimates were 71% (95% CI 61-78) and 46% (95% CI 36-56) for chemotherapy and surveillance, respectively.  Other ongoing adjuvant trials are also highlighted below.

One must recognize that there is also a higher proportion of upper tract urothelial carcinoma in metastatic disease trials than one might initially suspect.  There are many reasons for this that extend beyond the possibility of upper tract urothelial carcinoma having a potentially more aggressive natural history.  For instance, upper tract urothelial carcinoma patients may have a higher proportion with chronic kidney injury, resulting in eligibility and inclusion in trials focused on enrollment of cisplatin-ineligible patients.  For example, in KEYNOTE 052,12 a first-line trial for cisplatin-ineligible patients with metastatic disease, 19% of patients had upper tract disease and received pembrolizumab.  Even more notable was cohort 2 of the EV-201 trial, where 43% of patients harbored metastatic upper tract urothelial carcinoma, and these patients received 2nd line enfortumab vedotin.13  There is also a higher rate of FGFR alteration in upper tract urothelial carcinoma patients, as mentioned above, so it is not surprising that 23% of enrolled patients had upper tract disease in the trial leading to the accelerated FDA approval of erdafitinib.14  As upper tract urothelial carcinoma patients are not often specifically targeted in clinical trial design for patients with metastatic disease, I will not be able to highlight any distinct trials for the metastatic disease setting.

There are not many clinical trials designed specifically for patients with upper tract urothelial carcinoma, but there are a few, and they tend to span the disease spectrum from non-muscle invasive disease to neoadjuvant and adjuvant therapy.  Given the uniqueness and the rarity of this upper tract urothelial carcinoma, we clearly require more information and improved treatment options for our patients with this disease.  Please see below for more clinical trial information and sites of accessibility for your patients. 

Ongoing Highlighted trials focused on patients with Upper Tract Urothelial Carcinoma

  • ENLIGHTED – Phase 3 trial of Padeliporfin Soluble-Vascular Targeted Photdynamic Therapy on low grade disease with induction and maintenance (NCT04620239)
  • NAUTICAL – Feasibility, pilot trial of neoadjuvant gemcitabine with cisplatin or carboplatin (NCT04574960)
  • Randomized phase 3 trial of neoadjuvant chemotherapy with or without durvalumab (NCT04628767)
  • Phase 2 study of neoadjuvant gemcitabine/cisplatin with Toripalimab (PD-1 inhibitor) in patients with high-grade upper and lower tract muscle-invasive urothelial carcinoma (NCT04099589)
  • Phase 1 trial of neoadjuvant Infigratinib (NCT04228042)
  • URANUS – Randomized phase 2 trial of neoadjuvant versus adjuvant chemotherapy (NCT02969083)
  • Randomized, phase 3 trial of adjuvant Infigratinib vs. placebo in patients with FGFR3 altered upper or lower tract disease (NCT04197986)

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington


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