EAU 2021: Update on EAU-Guidelines on Management of Upper Tract Urothelial Cancer

(UroToday.com) The joint session of the European Association of Urology (EAU) and the Japanese Urological Association at the 2021 EAU virtual annual meeting included a presentation by Dr. Morgan Roupret highlighting the updated guidelines on the management of upper tract urothelial carcinoma. This update was published in 2020 in European Urology.1


Dr. Roupret started by emphasizing that among patients with upper tract urothelial carcinoma, there is new hope for the future, specifically:

  1. Molecular characterization: it matters
  2. Perioperative systemic chemotherapy/immunotherapy
  3. Avoiding under-treatment offers kidney sparing strategies to the appropriate patients
  4. Single post-operative dose intravesical chemotherapy

Urothelial carcinoma of the bladder and upper tract are disparate twins, in that bladder urothelial carcinoma and upper tract urothelial carcinoma share many features, but they are distinct diseases: there are practical, anatomical, biological, and molecular differences that warrant consideration in clinical decision-making:

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Clinicians should suspect hereditary upper tract urothelial carcinoma given that the incidence of a hereditary aspect is present in 10-20% of cases, and upper tract urothelial carcinoma is part of the HNPCC tumor spectrum (1-28% lifetime risk). Additional features that may suggest a hereditary component include patients < 60 years of age and a personal history of HNPCC-spectrum cancers. With regards to genetic mutations, MSI2/6 are the most frequent mutations associated with upper tract urothelial carcinoma and typically associated with high-grade tumors, inverted growth, deep pushing borders, and a lymphocyte infiltrative pattern. Lynch syndrome is also associated with an increased risk of upper tract urothelial carcinoma, with a recent study reporting the molecular subtype classification of these patients.2 Among 41 Lynch syndrome-associated urothelial carcinomas, these were diagnosed at a mean age of 61 years with 59% of patients being women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome-associated urothelial carcinomas as urothelial-like tumors with only 20% being genomically unstable, basal/SCC-like, or other subtypes. Ultimately, this study suggests that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch-repair defective subset.

With regards to perioperative chemotherapy, Dr. Roupret highlighted the important phase III POUT trial published last year in the Lancet.3 Eligible patients had received a radical nephroureterectomy for upper tract urothelial carcinoma, were postoperatively staged with either muscle-invasive (pT2–pT4, pNany) or lymph node-positive (pTany, pN1–3) M0 disease with predominantly transitional cell carcinoma histology, and were fit to receive adjuvant chemotherapy within 90 days of surgery. Patients were randomized 1:1 to receive either surveillance or adjuvant chemotherapy, with a primary endpoint of DFS defined as time from randomization to either first recurrence in the tumour bed, first metastasis, or death from any cause. There were 261 patients included in the trial, including 129 patients randomized to surveillance and 132 to chemotherapy. There were 60 (47%) DFS events in the surveillance cohort and 35 (27%) in the chemotherapy cohort; as such, the unadjusted HR was 0.45 (95%CI 0.30-0.68) in favor of chemotherapy (log-rank p = 0.0001). The three-year DFS rate was 46% for surveillance (95%CI 36-56) and 71% for chemotherapy (95%CI 61-78):

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The pros of a neoadjuvant chemotherapy approach for upper tract urothelial carcinoma are that the patient has a better renal function (with two kidneys in situ) and there is better evidence in urothelial carcinoma of the bladder for clinical benefit. The cons of this approach are that there is no definitive pathology preoperatively, and it is difficult to diagnose and stage patients accurately, thus some patients are at risk of overtreatment. Currently, there are no designative trials for PD-1 inhibitors for patients with upper tract urothelial carcinoma, however, several large urothelial carcinoma inclusive trials have upper tract urothelial carcinoma enrolled, including IMvigor 210 (21% upper tract urothelial carcinoma), IMvigor 211 (27% upper tract urothelial carcinoma) and KEYNOTE 045 (14% upper tract urothelial carcinoma).

When considering patients for nephron-sparing surgery, it is important to delineate sub-optimal versus over treatment according to Dr. Roupret. As such, we must rely on risk stratification algorithms, with the following proposal for risk stratifying upper tract urothelial carcinoma provided by Dr. Roupret:4

POUT trial.jpg 

Finally, Dr. Roupret notes that the EAU guidelines suggest that a postoperative instillation of chemotherapy is recommended after radical nephroureterectomy to avoid subsequent bladder recurrence.1 Also, of interest in the chemoablation disease space for upper tract urothelial carcinoma, is the recently published OLYMPUS trial.5 This trial included 71 patients that received six once-weekly instillations of UGN-101 as an induction course. Among the 71 patients who received at least one dose, 42 patients (59%, 95% CI 47-71%) had a complete response at the time of primary disease evaluation. Of the remainder, 8 (11%) had a partial response, 12 (17%) had no response, 6 (8%) had newly diagnosed high-grade disease, and 3 (4%) had an indeterminate response. As such, this option may be feasible for patients with low-grade upper tract urothelial carcinoma.

Presented by: Morgan Roupret, MD, PhD, Pitie-Salpetriere Academic Hospital, Assistance Publique-Hopitaux de Paris, Paris, France

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

References:

  1. Roupret M, Babjuk M, Capoun O, et al. European Association of Urology Guidelines on Upper Tract Urothelial Carcinoma: 2020 Update. Eur Urol 2020 Jun 24:S0302-2838(20)30427-9.
  2. Therkildsen C, Eriksson P, Hoglund M, et al. Molecular subtype classification of urothelial carcinoma in Lynch Syndrome. Mol Oncol. 2018 Aug;12(8):1286-1295.
  3. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): A phase 3, open-label, randomized controlled trial. Lancet 2020 Apr 18;395(10232):1268-1277.
  4. Roupret M, Colin P, Yates DR. A new proposal to risk stratify urothelial carcinomas of the upper urinary tract (UTUCs) in a predefinitive treatment setting: Low-risk versus high-risk UTUCs. Euro Urol 2014;66(2):181-183.
  5. 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 Jun;21(6):776-785.
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