The primary issue in this patient population is renal function. Work by multiple groups notes that even before radical nephroureterectomy, >50% of patients have an eGFR <60, which would make them cisplatin ineligible. Naturally, that number worsens after radical nephroureterectomy (RNU) – as high as 80% after surgery will be cisplatin-ineligible:
This plays an important role in the timing and decision to give systemic therapy.
In the neoadjuvant setting, there have been two studies that support its use. The first is the EORTC-ACRIN 8141 study, an open-label nonrandomized trial assessing the role of gemcitabine-cisplatin in cis-eligible patients (and gem-carboplatin in ineligible patients) prior to RNU. The study protocol and accrual are seen below:
Patients with high-grade tumor OR positive high-grade cytology with a visually confirmed tumor. They met their primary endpoint for arm 1 but did not accrue enough patients for arm 2 (gem/carbo). 80% of patients completed treatment, and they had a 14% complete response (CR) rate and >60% downstaging rate (to <= pT1).
In another study, which was presented as a late-breaking abstract at AUA 2019, Coleman et al. assessed gem-cis x 4 cycles prior to RNU or distal ureterectomy for high-risk localized UTUC. Histologically confirmed cT2-4N0M0 UTUC were included. They found a 58% pathologic downstaging (<pT2N0) and 19% CR rate, similar to the prior study. More importantly, the pathologic response was associated with improved survival.
So, neoadjuvant chemotherapy (NAC) should be considered upfront in cis-eligible patients. However, in this patient, treated at a community hospital, he had a RNU – final pathology was 3 cm pT4N1 high-grade urothelial carcinoma (UC) with LVI, but negative surgical margins.
As mentioned earlier, the biggest issue is that after RNU, only ~20% of patients are cis-eligible. There are numerous nomograms that can help predict the risk of recurrence based on pathology and clinical staging, and these can be used to identify patients at highest risk of recurrence:
In this setting, the POUT study (presented at 2018 GU ASCO) is the only randomized trial. It looked at adjuvant chemotherapy (gem-cis if eligible, gem-carbo is not) vs. surveillance in patients at high risk of recurrence – pT2-4N1-3, GFR > 30. The trial was stopped early as it met its primary endpoint – disease-free survival (DFS) and metastasis-free survival (MFS) were both significantly improved with adjuvant chemotherapy. However, the effect was only in patients treated with cisplatin, not carboplatin.
However, Dr. Margulis notes that POUT does not demonstrate superiority over neoadjuvant chemotherapy – so NAC should still be the preferred approach.
Presented by: Vitaly Margulis, MD, Associate Professor of Urology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX
Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA