EAU 2021: Optimal Timing of Perioperative Systemic Therapy for High-Risk Upper Urinary Tract Cancer

(UroToday.com) The Controversies in Onco-Urology session at the European Association of Urology 2021 virtual annual meeting included a presentation by Dr. Cedric Poyet who discussed the optimal timing of perioperative systemic therapy for high-risk upper tract urothelial carcinoma. Dr. Poyet notes that the definition of high-risk upper tract urothelial carcinoma includes cM0, pT2-T4 pN0-N3 or pTanyN1-N3, and high-grade disease. The goal of perioperative systemic therapy for high-risk upper tract urothelial carcinoma is to treat any potential micrometastasis and reduce the risk of recurrence and progression, which is a similar concept to bladder urothelial carcinoma. One of the main clinicopathological differences between upper tract urothelial carcinoma and bladder cancer is that 75% of patients with bladder cancer present with non-muscle invasive bladder cancer, whereas 60% of patients with upper tract urothelial carcinoma present with invasive disease.

Dr. Poyet notes that there is a strong rationale for neoadjuvant chemotherapy, given that many patients are ineligible for chemotherapy after radical nephroureterectomy due to renal insufficiency. Therefore, there is a rationale for chemotherapy before further loss of renal function, suggesting that treatment of micrometastasis with full dose cisplatin-based chemotherapy is optimal prior to radical nephroureterectomy and removal of relevant nephrons. Extrapolating from the bladder urothelial carcinoma data, there is additional rationale for neoadjuvant chemotherapy for upper tract urothelial carcinoma, as well as retrospective studies suggesting promising results with downstaging and lower progression rates.

A previously published systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma included 482 patients receiving cisplatin-based or non-cisplatin-based adjuvant chemotherapy after nephroureterectomy and 1300 patients receiving nephroureterectomy alone1. Across three cisplatin-based studies, the pooled hazard ratio for overall survival (OS) was 0.43 (95% CI 0.21-0.89; p=0.023) compared with those who received surgery alone. For neoadjuvant chemotherapy, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤ 93%. As follows is the DFS Forest plot from this study noting an HR of 0.41 (95% CI 0.22-0.76):

 

Poyet_EAU21_figure1 

Dr. Poyet then discussed the POUT trial2, an adjuvant setting phase III trial for upper tract urothelial carcinoma that has changed the landscape of treatment for locally advanced disease. Eligible patients who 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 tumor 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):

Poyet_EAU21_figure2 

Based on the aforementioned data, the EAU guidelines for upper tract urothelial carcinoma state that clinicians should offer post-operative systemic platinum-based chemotherapy to patients with muscle-invasive upper tract urothelial carcinoma (recommendation: strong).

A recently published study assessed the feasibility of neoadjuvant pembrolizumab before radical nephroureterectomy among patients with upper tract urothelial carcinoma (PURE-02 trial), which included 10 patients undergoing 3 courses of 200 mg pembrolizumab before radical nephroureterectomy3. Among these 10 patients, one had a complete clinical response, two had disease progression, and 6 of 7 patients that were non-responders underwent radical nephroureterectomy. Based on these results, Dr. Poyet suggests that pembrolizumab did not appear to be a promising long-term treatment strategy.

Dr. Poyet offered the following concluding and summary statements from his talk on perioperative management of upper tract urothelial carcinoma:

  • Peri-operative systemic treatment for upper tract urothelial carcinoma is of high relevance
  • Cisplatin-based chemotherapy agents have the most evidence, especially in the adjuvant setting
  • Due to kidney function deterioration after radical nephroureterectomy, neoadjuvant therapy is attractive and extrapolations from bladder urothelial carcinoma is reasonable
  • Immunotherapy should be considered for patients, especially those that are ineligible for chemotherapy

Presented By: Cedric Poyet, MD, PD Dr. med., University Hospital Zurich, Zurich, Switzerland

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. Leow JJ, Martin-Doyle W, Fay AP, et al. A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol. 2014 Sep;66(3):529-541.
  2. 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.
  3. Necchi A, Martini A, Raggi D, et al. A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk, upper tract urothelial carcinoma: PURE-02. Urol Oncol. 2021 Jun 16;S1078-1439(21)00220-9.
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