Neoadjuvant systemic therapy in patients undergoing nephroureterectomy for urothelial cancer: a multidisciplinary systematic review and critical analysis.

INTRODUCTION: The benefit of neoadjuvant systemic therapy (NAST) is not yet supported by randomized controlled trials in upper tract urothelial carcinoma (UTUC), but the evidence is increasing. This narrative systematic review was conducted to evaluate the available evidence on the role of NAST in patients undergoing radical nephroureterectomy (RNU) for UTUC. EVIDENCE ACQUISITION: We searched for all relevant articles or conference abstracts published and indexed in PubMed, Embase, and Scopus on July 19, 2021. The study was reported according to the PRISMA criteria and designed within the PICOS framework. We included studies comparing patients with non-metastatic UTUC who received neoadjuvant chemotherapy (NAC) or immunotherapy (NAI) with patients who underwent definitive surgery alone or surgery plus adjuvant systemic therapy. Prospective uncontrolled studies were also included. EVIDENCE SYNTHESIS: We identified 27 reports (NAC, N.=24 and NAI, N.=3) published between 2010 and 2021. Twenty of the 24 studies on NAC were retrospective comparative analyses, whereas the remaining four were prospective single-arm studies. One of the three NAI studies exclusively enrolled patients with UTUC. NAC was associated with improved survival and better pathological response relative to surgery alone, but there was no clear advantage when compared to surgery plus adjuvant chemotherapy. Overall, the drug-induced toxicity and risk of disease progression were acceptable but the inherent bias across study designs, inadequate reporting and heterogeneous definition of primary outcomes render it difficult to synthesize results, compare centers, and inform practice. CONCLUSIONS: The current level of evidence supporting NAST for UTUC is relatively low and the inability to predict responsiveness and thereby pinpoint the optimal candidates remains a major challenge. There is a need to compare NAST to adjuvant therapies using clearly defined primary endpoints as minimum reporting standards developed by a multidisciplinary team.