ESOU 2019: New Perspectives in Upper Tract Urothelial Cancer Treatment

Prague, Czech Republic (UroToday.com) Dr. Morgan Roupret, a recognized expert in the management of upper tract urothelial carcinoma (UTUC) and the senior author of the EAU guidelines, provided a talk on new perspectives in UTUC treatment. He had four main points that he spent the most time on, which I highlight below.

  1. Molecular characterization – it matters!
Genomic classification of all tumors and all GU tumors has been at the forefront of cancer research in the past few years. Within urology and urothelial disease, the molecular characterization of bladder cancer has received significant attention. These developments are likely to have a significant impact on our understanding of the disease and be important in the treatment paradigm for bladder cancer – early data already suggests it could help select appropriate treatments for patients muscle-invasive bladder cancer.

Yet, his main take-home point is that there is growing clinical and genomic information that UTUC and lower tract bladder cancer are not the same disease process, but rather distinct entities with some shared features. The slide below highlights some of the differences between the two:

UroToday ESOU19 UTUC twins

Indeed, as noted above, the fact that UTUC is part of the HNPCC (Lynch syndrome) and bladder cancer is not, indicates a slightly different development pathway. More recent work in this area has demonstrated that patients with microsatellite instability (MSI+) have higher grade tumors, inverted growth, deep pushing borders, and lymphocytic infiltrate. Work by Seth Lerner and Surena Matin (Moss et al. EU 2017) represents the first comprehensive genomic characterization of UTUC distinct from bladder cancer. This, amongst other work, will enable a better understanding of UTUC.

  1. Perioperative systemic therapy – chemotherapy and immunotherapy.
The results of the POUT study (presented by Dr. Jones earlier in this session) were a landmark study demonstrating, for the first time, the oncologic benefit of perioperative chemotherapy in patient with advanced localized UTUC following nephroureterectomy. This is difficult to do, considering the rarity of the condition – and he lauds them on the completion. He also alluded to, as Dr. Jones did, the plans for POUT 2, which looks at a combination of chemotherapy and immunotherapy vs. chemotherapy alone.

He briefly noted that he still feels that neoadjuvant therapy would be better than adjuvant therapy, as these relatively elderly patients would likely tolerate therapy and kidney injury better prior to nephrectomy rather than after.  However, due to the lack of definitive pathology, grade and staging, he understands the rationale for the POUT authors to start with adjuvant therapy.

He does note some neoadjuvant studies in the process of starting – including the completed phase II ECOG-AGRIN EA 8141 study demonstrating  14% pCR response to NAC and 62% downstaging to <= pT1. He also acknowledged the URANUS study by the EUOG, which is estimated to accrue by Oct 2020.

While immune-checkpoints have not specifically been assessed in UTUC, he points out that many of the ICI studies for metastatic urothelial cancer studies had 14-27% of UTUC patients included. There were higher objective response rates in patients with bladder cancer than in UTUC, but patients with bladder cancer had higher tumor mutational burden, higher PD-L1 expression and increased the frequency of genomically unstable tumors.  Hence, no conclusions can be drawn. POUT 2 may shed some more light on this.

  1. Avoid undertreatment – offer kidney-sparing treatment to appropriate patients.
He also noted that the EAU guidelines updated expanded eligibility of conservative endoscopic management of UTUC to tumors up to 2 cm in size (previously 1 cm). However, he notes that while endoscopic management may be suboptimal, radical nephroureterectomy may be overtreatment for these larger tumors. He touched on the CellVizio data that has previously been presented as a method to perhaps better select patients for endoscopic treatment vs. nephroureterectomy.

  1. A single postoperative dose of intravesical chemotherapy after flexible URS
Indeed, a systematic review demonstrated that, from 7 studies, patients undergoing diagnostic URS prior to nephroureterectomy had a higher rate of bladder recurrences (HR 1.56, p < 0.001)1. Yet, despite the growing concern, there are already guidelines in the EAU for this scenario – and they recommend antegrade instillation of BCG or MMC in the upper tract following UTUC endoscopic treatment and a single dose of chemotherapy in the bladder following radical nephroureterectomy. Unfortunately, very few people adhere to this, and this needs to be improved upon. 


Presented by: Morgan Roupret, MD, Ph.D, Faculty of Medicine, Pierre and Marie Curie University, Faculté de médecine Pierre et Marie Curie, Paris, France

Written by: Thenappan Chandrasekar, MD. Clinical Instructor, Thomas Jefferson University, Twitter: @tchandra_uromd, @TjuUrology, at the 16th Meeting of the European Section of Oncological Urology, #ESOU19, January 18-20, 2019, Prague, Czech Republic

References:
1. Marchioni et al. (2017) Impact of diagnostic ureteroscopy on intravesical recurrence in patients undergoing radical nephroureterectomy for upper tract urothelial cancer: a systematic review and meta‐analysis. BJU, 120 (3), 313-319. 
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