Most urothelial cancers occur in the lower urinary tract, but 5-10% originate in the upper urinary tract, including the calyces, renal pelvis, and ureter. 1 Although upper urinary tract and lower urinary tract urothelial carcinoma may have similar histology, the natural course is different, and upper urinary tract diseases often have a higher incidence of local infiltration at the time of diagnosis. 2 The risk factors for urothelial cancer of the upper urinary tract are similar to those of the lower urinary tract, but there are some unique risk factors related to environmental exposure. For example, the incidence of upper urinary tract urothelial cancer in Taiwan is extremely high. Because water is contaminated with arsenic, the ratio of male to female is 1:2, which is counterintuitive and is called black foot disease. In addition, in Taiwan and Balkan countries, contact with aristolochia herbs (fangfang and clematis) can cause cancer, leading to progressive renal fibrosis and upper urinary tract urothelial cancer. 4, 5
The biology of upper urinary tract urothelial cancer is usually related to Lynch syndrome. Lynch syndrome is an autosomal dominant genetic disease with impaired DNA mismatch repair, leading to colon cancer, endometrial cancer, ovarian cancer, High risk of stomach cancer and upper urinary tract urothelial cancer. 6 However, Lynch syndrome is not a common event, and estimates for the entire population range from 1:2000 to 1:660.7. For most practicing clinicians, patients with Lynch syndrome and upper urinary tract urothelial cancer are rarely encountered. However, somatic fibroblast growth factor 3 (FGFR3) mutations are very common, and whole-exome sequencing of DNA and RNA shows that FGFR3 is the most common mutated gene. 8 Interestingly, the incidence of FGFR3 mutation in upper urothelial carcinoma was found to be 74%. Surprisingly, low-grade disease (92%) is even higher than high-grade disease (60%).
Urothelial carcinoma of the upper urinary tract poses some unique challenges to the surgical treatment of urology. Intravesical administration of Bacille Calmette-Guerin (BCG) and Mitomycin C is usually used to reduce the risk of recurrence and progression of carcinoma in situ and non-muscular invasive bladder cancer, but it is clinically effective and dosing for upper urinary tract diseases The method is controversial. The local treatment of urothelial carcinoma of the upper urinary tract can be carried out in a variety of ways: 1) directly into the bladder, hoping to use indwelling ureteral stent for vesicoureteral reflux, 2) retrograde perfusion through an open ureteral catheter, or 3 ) The percutaneous nephrostomy tube is perfused anteriorly through the ureter. Another challenge faced by urologists is that approximately 50% of patients with upper urinary tract urothelial cancer will develop lower urinary tract disease, many of which are thought to be implanted distally.
For the purpose of this article, we will focus more on clinical trials of systemic treatments. The first case is neoadjuvant therapy. It is inferred from the supporting data of bladder urothelial cancer, and the general logic supports its use in upper urinary tract diseases. This is because compared with the adjuvant treatment after radical nephroureterectomy, the practical advantage of having twice as many nephrons before surgical resection. Since cisplatin combined with chemotherapy is commonly used and its nephrotoxic side effects are well known, neoadjuvant therapy seems to be the first choice when possible. ECOG-ACRIN 8141 is a phase 2 open-label trial for the treatment of gemcitabine/cisplatin patients with a complete response rate of 14%. 9 Similarly, another multicenter trial also treated patients with neoadjuvant gemcitabine/cisplatin, which resulted in a pathological downstage response of 60%, defined as <pT1N0.10. The 2-year progression-free survival rate was 76%, which is quite impressive. The following focuses on other neoadjuvant trials of chemotherapy, molecular targeted therapy, and combined immunotherapy.
The adjuvant POUT trial is a multicenter randomized controlled trial from the United Kingdom that provides the most powerful data to support perioperative chemotherapy for upper urothelial cancer. The trial recruited 261 patients with upper urinary tract disease with pT2-4N0-3M0 or pTanyN1-3M0 after radical nephroureterectomy, and these patients were randomly assigned to adjuvant chemotherapy and monitoring. Specifically, the disease-free survival rate after adjuvant therapy with gemcitabine/cisplatin or gemcitabine/carboplatin is better than monitoring, with an HR of 0.45, 95% CI 0.30-0.68, p=0.0001.11. The estimated three-year event-free survival rate is 71 % (95% CI 61-78 for chemotherapy and surveillance, respectively) and 46% (95% CI 36-56). The following also highlights other ongoing auxiliary trials.
People must realize that in metastatic disease trials, the proportion of upper urinary tract urothelial cancer is also higher than initially suspected. There are many reasons for this situation, beyond the possibility of upper urinary tract urothelial cancer with a potentially more aggressive natural course. For example, patients with urothelial cancer of the upper urinary tract may have a higher percentage of chronic kidney injury, leading to qualifying and being included in trials that focus on recruiting patients who do not qualify for cisplatin. For example, in a first-line trial of KEYNOTE 052,12 in patients with metastatic disease not eligible for cisplatin, 19% of patients had upper urinary tract disease and received pembrolizumab. More noteworthy is the EV-201 trial cohort 2, in which 43% of patients had metastatic upper urothelial carcinoma, and these patients received second-line enfortumab vedotin. 13 Patients with upper urinary tract urothelial cancer also have a higher FGFR change rate. As mentioned above, it is not surprising that 23% of the enrolled patients in the trial have upper urinary tract disease, which led to the accelerated approval of the FDA Datinib. 14 Since patients with upper urinary tract urothelial cancer are usually not the specific targets of patient-specific clinical trials for metastatic disease, I will not be able to emphasize any unique trials that target the metastatic disease environment.
There are not many clinical trials specifically designed for patients with upper urinary tract urothelial cancer, but there are some, and they often span the spectrum of diseases from non-muscle invasive diseases to neoadjuvant and adjuvant therapies. In view of the uniqueness and rarity of this upper urinary tract urothelial cancer, we obviously need more information and improved treatment plans to treat our disease. Please see below for more clinical trial information and the websites your patients can visit.
Ongoing key trials focus on patients with urothelial cancer of the upper urinary tract
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