Jeffrey J Leow1, Yew Lam Chong2, Steven L Chang3, Begoña P Valderrama4, Thomas Powles5, Joaquim Bellmunt6. 1. Department of Urology, Tan Tock Seng Hospital, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Division of Urology and Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 2. Department of Urology, Tan Tock Seng Hospital, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. 3. Division of Urology and Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 4. Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain. 5. Barts Cancer Institute, Barts Health and the Royal Free NHS Trusts, London, UK. 6. Beth Israel Deaconess Medical Center and PSMAR-IMIM Research Lab, Harvard Medical School, Boston, MA, USA. Electronic address: jbellmun@bidmc.harvard.edu.
Abstract
CONTEXT: To improve the prognosis of upper tract urothelial carcinoma (UTUC), clinicians have used neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) before or after radical nephroureterectomy (RNU). Despite some new data, the evidence remains mixed on their efficacy. OBJECTIVE: To update the current evidence on the role of NAC and AC for UTUC. EVIDENCE ACQUISITION: We searched for all studies investigating NAC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings up to February 2020. A systematic review and meta-analysis was performed. EVIDENCE SYNTHESIS: For NAC, the pooled pathologic complete response rate (≤ypT0N0M0) was 11% (n = 811) and pathologic partial response rate (≤ypT1N0M0) was 43% (n = 869), both across 14 studies. Across six studies, the pooled hazard ratios (HRs) were 0.44 (95% confidence interval [CI]: 0.32-0.59, p < 0.001) for overall survival (OS) and 0.38 (95% CI: 0.24-0.61, p < 0.001) for cancer-specific survival (CSS) in favor of NAC. The evidence for NAC is at best level 2. As for AC, there was a benefit in OS (pooled HR 0.77; 95% CI: 0.64-0.92, p = 0.004 across 14 studies and 7983 patients), CSS (pooled HR 0.79; 95% CI: 0.69-0.91, p = 0.001 across 18 studies and 5659 patients), and disease-free survival (DFS; pooled HR 0.52; 95% CI: 0.38-0.70 across four studies and 602 patients). While most studies were retrospective (level 2 evidence), there were two prospective randomized trials providing level 1 evidence. There are currently four phase 2 trials on neoadjuvant immunotherapy and three phase 2 trials on adjuvant immunotherapy for UTUC. CONCLUSIONS: NAC for UTUC confers a favorable pathologic response and tumor downstaging rate, and an OS and CSS benefit compared with RNU alone. AC confers an OS, CSS, and DFS benefit compared with RNU alone. Currently, the evidence for AC appears stronger (with positive level 1 evidence) than that for NAC (at best level 2 evidence). Limited data are available for chemoimmunotherapy approaches, but preliminary data support an active research investment. PATIENT SUMMARY: After a comprehensive search of the latest studies examining the role of neoadjuvant and adjuvant chemotherapy for upper tract urothelial cancer, the pooled evidence shows that perioperative chemotherapy was beneficial for prolonging survival; however, the evidence for adjuvant chemotherapy was stronger than that for neoadjuvant chemotherapy.
CONTEXT: To improve the prognosis of upper tract urothelial carcinoma (UTUC), clinicians have used neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) before or after radical nephroureterectomy (RNU). Despite some new data, the evidence remains mixed on their efficacy. OBJECTIVE: To update the current evidence on the role of NAC and AC for UTUC. EVIDENCE ACQUISITION: We searched for all studies investigating NAC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings up to February 2020. A systematic review and meta-analysis was performed. EVIDENCE SYNTHESIS: For NAC, the pooled pathologic complete response rate (≤ypT0N0M0) was 11% (n = 811) and pathologic partial response rate (≤ypT1N0M0) was 43% (n = 869), both across 14 studies. Across six studies, the pooled hazard ratios (HRs) were 0.44 (95% confidence interval [CI]: 0.32-0.59, p < 0.001) for overall survival (OS) and 0.38 (95% CI: 0.24-0.61, p < 0.001) for cancer-specific survival (CSS) in favor of NAC. The evidence for NAC is at best level 2. As for AC, there was a benefit in OS (pooled HR 0.77; 95% CI: 0.64-0.92, p = 0.004 across 14 studies and 7983 patients), CSS (pooled HR 0.79; 95% CI: 0.69-0.91, p = 0.001 across 18 studies and 5659 patients), and disease-free survival (DFS; pooled HR 0.52; 95% CI: 0.38-0.70 across four studies and 602 patients). While most studies were retrospective (level 2 evidence), there were two prospective randomized trials providing level 1 evidence. There are currently four phase 2 trials on neoadjuvant immunotherapy and three phase 2 trials on adjuvant immunotherapy for UTUC. CONCLUSIONS: NAC for UTUC confers a favorable pathologic response and tumor downstaging rate, and an OS and CSS benefit compared with RNU alone. AC confers an OS, CSS, and DFS benefit compared with RNU alone. Currently, the evidence for AC appears stronger (with positive level 1 evidence) than that for NAC (at best level 2 evidence). Limited data are available for chemoimmunotherapy approaches, but preliminary data support an active research investment. PATIENT SUMMARY: After a comprehensive search of the latest studies examining the role of neoadjuvant and adjuvant chemotherapy for upper tract urothelial cancer, the pooled evidence shows that perioperative chemotherapy was beneficial for prolonging survival; however, the evidence for adjuvant chemotherapy was stronger than that for neoadjuvant chemotherapy.
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