UTUC accounts for 5-10% of urothelial malignancies, of which 60% are invasive at disease presentation. Radical nephroureterectomy remains the standard of care for localized and invasive disease. The 5-year overall survival for pT2-pT3 disease is <50% and a dismal <10% for pT4 disease. It is important to note that due to a paucity of evidence, the benefit of perioperative chemotherapy is extrapolated from bladder cancer. However, although UTUC histology is similar to bladder cancer, embryonic origin, genomic and epigenomic features, staging and prognosis differ between the two. That being said, urothelial cancers appear to be quite sensitive to chemotherapy. So, in addition to the extrapolation from the bladder cancer world, there is new emerging data and strong rationale for perioperative chemotherapy in UTUC.
When it comes to perioperative chemotherapy, there are several pros and cons with regards to neoadjuvant or adjuvant treatment:
The main difference in this list vs. the list of neoadjuvant chemotherapy (NAC) and/or adjuvant chemotherapy (AC) for bladder cancer is the consideration of renal function after nephrectomy – adjuvant therapy is given in the setting of a solitary kidney (and often after renal insult), so eligibility for chemotherapy may be affected. NAC is given in the setting of two healthy kidneys and normal renal function.
There had been numerous population level analyses and retrospective series demonstrating the benefit of adjuvant chemotherapy over no chemotherapy, but the POUT trial was the first phase III RCT reported for adjuvant chemotherapy specifically for patients with UTUC.1 For this trial, patients (maximum n=345) that had a WHO performance status 0-1, and were ≤90 days post nephroureterectomy were randomized (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance. The primary endpoint was disease-free survival (DFS), and patients had cross sectional imaging and cystoscopy every 6 months for the first 2 years, then annually to 5 years. There were 248 patients included in the trial, including 123 patients randomized to surveillance and 125 to chemotherapy at 57 UK centers. In October 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected to date met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Patients were a median 69 years of age (range 36-88), 30% had pT2 disease, 65% pT3, and 91% pN0. There were 47 (38.2%) DFS events in the surveillance cohort and 29 (23.2%) in the chemotherapy cohort; the unadjusted HR was 0.47 (95%CI 0.29-0.74) in favor of chemotherapy (log-rank p= 0.0009). Two year DFS was 51% for surveillance (95%CI 39-61) and 70% for chemotherapy (95%CI 58-79). Metastasis-free survival also favored chemotherapy, with a HR of 0.49 (95%CI 0.30-0.79, p=0.003).
However, Dr. Sridhar does note the following from the POUT study:
- Only 66% of patients received Gem/Cis
- Only 68% of patients completed chemotherapy
- 13% switched to Gem/Carbo
- Gem/Cis sub-analysis is where the greatest benefit was at – so patients have to get the cisplatinum-based chemotherapy to benefit!
Leow et al. in a pooled analysis of 2 retrospective series, found a 59% risk reduction in DFS with NAC over no chemotherapy (HR 0.41, p = 0.005).2 Despite the retrospective nature, there is strong belief this represents a real finding. Other NAC series have reported pCR rates of 9-14% and pathologic downstaging rates between 50-60%.
The ECOG-ACRIN 8141 study asked this question. Patients with high-risk localized RNU are randomized to either advanced MVAC (if CrCl > 50) or Gem-Carbo (if CrCl < 50) prior to scheduled RNU + LND, and the primary endpoint is pCR. Unfortunately, this was not randomized against no chemotherapy or even adjuvant chemotherapy. In AUA 2018, they presented the data – and found a 14% pCR rate and a 62% pathologic downstaging at the time of RNU. Recent data suggests that pathologic downstaging is more informative than pCR in UTUC, so these numbers are quite good!
This study demonstrated the feasibility of a NAC study in UTUC and the results are encouraging. There are now numerous ongoing trials of NAC:
URANUS was presented earlier at this meeting but is the only one comparing AC and NAC.
As mentioned earlier and in other talks, there is serious interest in immune checkpoint inhibitors for UTUC. Large early-phase immune checkpoint inhibitor trials in first-line metastatic urothelial carcinoma suggest the activity of checkpoint inhibitors in untreated patients. In KEYNOTE-052, pembrolizumab was associated with an ORR of 22% among UTUC patients, whereas in IMvigor 210, atezolizumab was associated with an ORR of 39%. There are several exciting immune checkpoint inhibitor trials ongoing:
Adjuvant immunotherapy trials:
Neoadjuvant immunotherapy trials:
At the end of the talk, she concluded by saying:
- UTUC patients are at high risk for recurrence
- Perioperative chemotherapy has a clear role in this patient population
- POUT confirms benefit of adjuvant therapy in the patients that can get it, but renal function decline may preclude chemotherapy
- NAC may be better tolerated and completed, result in pCR and downstaging – but more trials are needed
- Novel therapies, including immune checkpoint inhibitors and FGFR3 inhibitors, are in the pipeline and being tested
Presented by: Srikala Sridhar, MD, MSc, FRCPC, Associate Professor within the Department of Medicine, Division of Medical Oncology at the University of Toronto, Medical Advisory and Research Board, Princess Margaret Hospital, Toronto, Ontario
Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona Spain, March 15-19, 2019.
- Birtle A, Johnson M, Kockelbergh R, et al. Results of POUT: A phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). EAU 2018 abstr 1017.
- Leow, J., Martin-Doyle, W., Fay, A., Choueiri, T., Chang, S., & Bellmunt, J. (2014). A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma. European Urology, 66(3), 529-541. doi: 10.1016/j.eururo.2014.03.003