Upper tract urothelial carcinoma case illustrates rapidly changing treatment landscape

The Case

Benjamin J. Martin, MD

A 65-year-old man presented in early 2019 with gross painless hematuria. He has a history of T1 high-grade urothelial carcinoma of the bladder, status post transurethral resection of bladder tumor (TURBT) times 2, each followed by an induction 6-week course of BCG and maintenance; he experienced good response with no recurrence documented for more than a year. Unfortunately, he has been lost to follow-up since his last negative office surveillance cystoscopy approximately 12 months prior to this episode.

• Medications: Amlodipine (Norvasc), lisinopril, atorvastatin (Lipitor), pantoprazole (Protonix)

• Allergies: no known drug allergies

• Past medical history: hypertension, hypercholesterolemia, gastroesophageal reflux disease, psoriasis

• Social history: former smoker (40 pack-years), quit after second TURBT

• Physical exam: unremarkable, normal genitourinary exam and digital rectal exam

• Glomerular filtration rate (GFR): 66 mL/min/1.73 m²

• CT urogram showed 4-cm ill-defined hypoenhancement of the right lower pole, with subtle perinephric stranding. There was no lymphadenopathy.

• Cystoscopy: no bladder recurrence

• Right ureteroscopy confirmed papillary lesion occupying the entire lower pole calyces.

• Urine cytology: positive for urothelial cancer

Discussion

We are all very familiar with the risk of local recurrence of high-grade urothelial cancer, but a recent meta-analysis of upper tract recurrence following radical cystectomy showed only a 0.75% to 6.4% risk.¹ A strong argument could have been made for a cystectomy at this patient’s first high-grade T1 recurrence post-BCG a few years ago. His recurrence was noted to be less than 3 cm in size, was unifocal, and no carcinoma in situ was present. If he had chosen the cystectomy route, he more than likely would have received standard-of-care neoadjuvant chemotherapy.

Would that have reduced his risk of upper tract disease?

The role of neoadjuvant chemotherapy for upper tract urothelial carcinoma has not been established to the same degree as it has for bladder cancer. Current National Comprehensive Cancer Network guidelines do not recommend it as first-line therapy.² A meta-analysis by Loew et al found support for both neoadjuvant and adjuvant chemotherapy in combination with radical nephroureterectomy, but the only randomized studies with level 1 evidence support adjuvant treatment.³

Endoscopic management is generally reserved for smaller, low-grade lesions. Mitomycin administered via a unique gel (Jelmyto) is a new FDA-approved option that allows for a nephron-sparing approach in patients with low-grade tumors of the upper tract.⁴ A direct biopsy of the renal pelvis tumor was not done in this patient, but based on the history and the imaging characteristics, it was thought to be more likely than not high-grade, invasive disease. He also had no contraindications to definitive surgery that would necessitate nephron sparing. However, it is important to differentiate low- versus high-grade disease in light of this new approval.

The patient underwent a right robotic-assisted total nephroureterectomy with extravesical bladder cuff excision in June 2019. His preoperative GFR was 66 mL/min/1.73 m², and immediately postoperatively, it had declined to 46 mL/min/1.73 m². The final pathology was read as a 5.3-cm high-grade urothelial cancer that invaded into the renal pelvis adipose tissue and renal parenchyma.

He was referred to medical oncology for adjuvant therapy. An fludeoxyglucose F 18–positron emission tomography (FDG PET) scan showed uptake in a few small pulmonary nodules and in portacaval lymph nodes, thought to be consistent with metastatic disease. With his reduced renal function, he was deemed not eligible for cisplatin-based therapy, which is included in the preferred regimens.²

Therefore, he was started on carboplatin and gemcitabine. Pancytopenia after 5 cycles necessitated a dose reduction; due to continued renal function decline, carboplatin was discontinued after the sixth cycle. A repeat PET scan at that time showed stable disease. The patient continued gemcitabine for 8 more cycles, but worsening renal function (GFR: 23) and thrombotic thrombocytopenic purpura caused cessation of therapy in August 2020. Repeat imaging confirmed progression of disease.

Pembrolizumab (Keytruda) is an FDA-approved monoclonal antibody immunotherapy directed against the PD-1 receptors on T cells. PD-L1 and PD-L2 ligands on tumor cells couple with T-cell PD-1 receptors to block T-cell function. By blockade of the PD-1 receptor, tumor-mediated immune suppression is prevented.⁵ Initial FDA approval required a PD-L1 expression combined positive score of 10% or more in the tumor tissue, but pembrolizumab may be used in patients regardless of PD-L1 expression if they are cisplatin ineligible, as is the case with this patient—although the objective response rate (ORR) is much less if the tumor has lower expression.

Enfortumab vedotin-ejfv (Padcev) is an antibody-drug conjugate against NECTIN4, which is increased on the cell surface of multiple subtypes of urothelial carcinoma. The phase 2 EV-201 trial (NCT03219333)included patients heavily pretreated with platinum-based agents and anti–PD-1/PD-L1 therapy, yet still showed an ORR of 44% and complete responses of 12%.⁶ Enfortumab vedotin is given intravenously on days 1, 8, and 15 of a 4-week cycle. Possible adverse events include fatigue, peripheral neuropathy, alopecia, rash, and decreased appetite. This patient opted for clinical trial and started therapy with enfortumab vedotin in September 2020. His renal function improved to 32 mL/min/1.73 m² on treatment. Imaging with FDG PET showed stable disease as of his last exam in May 2021.

In just a few short years, the treatment options for upper tract urothelial carcinoma have changed considerably. Urologists and medical oncologists should work together in a multidisciplinary fashion to tailor therapy to the specific needs of each patient. It should also be noted that upper tract urothelial tumors are a very common presentation for patients with Lynch syndrome. With that in mind, urologists need to be aware of genetic and somatic testing for Lynch syndrome and associated tumors, which include colorectal, upper gastrointestinal, endometrial, ovarian, and pancreatic cancers. Obviously, this can affect screening for these cancers and family counseling.

References

1. Picozzi S, Ricci C, Gaeta M, et al. Upper urinary tract recurrence following radical cystectomy for bladder cancer: a meta-analysis on 13,185 patients. J Urol. 2012;188(6):2046-2054. doi:10.1016/j.juro.2012.08.017

2. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 3.2021. Accessed May 31, 2021. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

3. Leow JJ, Chong YL, Chang SL, Valderrama BP, Powles T, Bellmunt J. Neoadjuvant and adjuvant chemotherapy for upper tract urothelial carcinoma: a 2020 systematic review and meta-analysis, and future perspectives on systemic therapy. Eur Urol. 2021;79(5):635-654. doi:10.1016/j.eururo.2020.07.003

4. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9

5. Crist M, Iyer G, Hsu M, Huang WC, Balar AV. Pembrolizumab in the treatment of locally advanced or metastatic urothelial carcinoma: clinical trial evidence and experience. Ther Adv Urol. 2019;11:1756287219839285. doi:10.1177/1756287219839285

6. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol. 2019;37(29):2592-2600. doi:10.1200/JCO.19.01140