SIU 2018: Adjuvant Therapy After Radical Nephroureterectomy: Where Is the Evidence

Seoul, South-Korea ( Badrinath Konety, MD as the final speaker in the UTUC instructional course, focused on the role of adjuvant therapy for UTUC after nephroureterectomy (RNU).  First and foremost, the difficulty in assessing the quality of studies already completed in this area (for perioperative chemotherapy) is that there are:

  • Variations in surgical technique (bladder cuff management, LND)
  • Variations in chemo regimen
  • Numbers and cycles of chemo administered
  • Variations in the definition of recurrence – this is a KEY point in assessing the studies
  • Many studies considered secondary bladder cancer as a recurrence – however, this probably should not be counted towards recurrence-free survival!
  • Inaccurate staging limits neoadjuvant chemotherapy decision
One of the main prospective studies assessing AC (adjuvant chemotherapy) following RNU was by Kwak et al. (Urology 2006). In that study, 32 patients with pT3 or pN+ disease received AC. Used MVAC or GC chemotherapy regimen. They demonstrated an overall survival benefit in patients who received AC vs. those who did not (72% vs. 18%). However, disease-free survival was no different – BUT, this included bladder recurrence!

A subsequent meta-analysis by Leow et al. (EU 2014) compared 482 patients who underwent RNU + AC vs. 1300 who underwent RNU alone. There was no significant difference in overall or disease-specific survival – there was a trend towards benefit, but not clinically significant. In a study by Necchi et al. (BJUI 2018) though, there was a survival benefit with AC regardless of whether patients were pT2N0 or pT3-4 disease (though it appeared to be slightly better in the pT3-4 patients). Seisen et al. (JCO 2017) demonstrated a survival benefit with AC as well using the NCDB database, with 5-year OS improving from 36% to 44%.

There is pretty strong evidence suggesting benefit with NAC (HR 0.41, p = 0.005) on meta-analysis – but the difficulty is selecting the right patient for it.

The most important randomized controlled (and only one to report so far) in this space is the POUT study. This was presented at AUA and ASCO this year. In this study, patients were randomized to either RNU alone or perioperative chemotherapy (adjuvant chemotherapy). The chemotherapy regimen was determined by creatinine clearance, so some patients received carboplatin instead of cisplatin. The regimen was either Gem-Cis or Gem-Carbo. Only patients with pT2-4N0 or pTanyN1-3M0 disease within 90 days of RNU and good performance status were included. This was an intent-to-treat analysis (ITT) and the primary endpoint was disease-free survival. They were powered to detect a 15% improvement in DFS.

This study was actually stopped early because, at their interim analysis, patients who received AC has a 19% survival benefit (70% vs. 51%, HR 0.47). While the OS analysis is ongoing, this was the first prospective study to demonstrate a significant survival benefit.

Per the study by Shirotake et al (JU 2014), MVAC is a better regimen than GC – so perhaps the POUT study results would have been even better with MVAC!

Xylinas et al. (EU 2012) looked at the impact of variant histology, regardless of perioperative chemotherapy – and there was no difference in outcomes. So patients with UTUC of all histologies should be treated with adjuvant therapy.

Presented by: Badrinath Konety, MD, MBA, Professor, Department Chair, Department of Urology, Dougherty Family Chair in Uro-Oncology and is Director of the Institute for Prostate and Urologic Cancers, Associate Dean for Strategy and Innovation, University of Minnesota, United States

Written By: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University Twitter: @tchandra_uromd, @TjuUrology at the 38th Congress of the Society of International Urology - October 4- 7, 2018 - Seoul, South Korea

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