(UroToday.com) Neoadjuvant chemotherapy (NAC) is the standard of care for muscle-invasive bladder cancer. However, upper tract urothelial carcinoma (UTUC) is not the same as bladder cancer, with a higher rate of invasive disease. The survival of high grade and high stage disease UTUC remains poor (Figure 1), and downstaging in urothelial cancer is highly predictive of improved survival1.
Figure 1 – Disease-specific survival rate in UTUC in relation to (A) pT stage, (B) grade1:
Platinum-based chemotherapy is most effective, but cisplatin requires adequate glomerular filtration rate (GFR). Nephroureterectomy reduces GFR by 24%, and depending on the GFR cutoff used to administer cisplatin-based chemotherapy2, the following can be seen:
- For GFR of 60 ml/min – 49% are eligible preoperatively while only 19% are eligible postoperatively
- For GFR of 45 ml/min – 80% are eligible preoperatively while only 55% are eligible postoperatively
NAC has also been shown to result in pathologic downstaging3 (Figure 2). And improve overall and disease-specific survival4 (Figure 3). A recent meta-analysis has also shown a clear benefit of NAC in both overall survival and cancer-specific survival5 (Figure 4).
Figure 2 – Pathologic tumor classification3:
Figure 3 - Disease-specific survival in relation to neoadjuvant chemotherapy in UTUC:
Figure 4 – Forest Plot of Studies Evaluating The Efficacy of Neoadjuvant Chemotherapy For UTUC on (a) Overall Survival (OS), (b) Cancer-Specific Survival (CSS)5
Lastly, the landmark POUT trial6, a phase 3, an open-label prospective randomized-controlled trial conducted at 71 hospitals in the UK, was discussed. This trial showed that Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. However, 40% of the enrolled patients were cisplatin-ineligible, and 21% of the patients had to cross over to being treated with carboplatin. These subsets of patients did not demonstrate a statistically significant benefit when treated with adjuvant chemotherapy (Figure 5).
Figure 5: Subgroup analysis of disease-free survival in the POUT trial:
In conclusion, outcomes for invasive UTUC are poor. There is enough evidence to suggest that perioperative cisplatin-based chemotherapy for UTUC works to improve survival. It is important to remember that there is a high rate of chronic kidney disease following radical nephroureterectomy. Therefore, NAC should be the logical choice to improve survival in UTUC patients. There is a need to conduct randomized trials to assess NAC for UTUC. The POUT-2 trial will target FGFR-3, assessing the role of immune-oncology (the PROOF trial7).
Presented by: Jen-Jane Liu, MD, Assistant Professor of Urology, School of Medicine, Oregon Health & Science University, Portland, Oregon
Written by: Hanan Goldberg, MD, MSc, Assistant Professor, Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, @GoldbergHanan during the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
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2. Kaag MG, O'Malley RL, O'Malley P, et al. Changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy. European urology 2010; 58(4): 581-7.
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7. Pal SK, Daneshmand S, Matin SF, et al. PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring FGFR3 alterations. Journal of Clinical Oncology 2020; 38(6_suppl): TPS600-TPS.