The objectives of this study are to evaluate the available literature regarding the oncologic effect of neoadjuvant and adjuvant chemotherapy in the treatment of patients with clinically non-metastatic upper tract urothelial carcinoma (UTUC) and locally advanced UTUC. We searched PubMed, Cochrane Library, and Scopus databases in November 2019, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We included studies that compared patients with non-metastatic UTUC who received either neoadjuvant or adjuvant chemotherapy with patients who underwent surgery alone. Subgroup meta-analyses were also performed for studies that investigated only locally advanced UTUC. Overall, 36 studies were included in the review of which 22 studies and 15,378 patients were eligible for the meta-analysis. Neoadjuvant chemotherapy (NAC) was associated with higher rates of pathological downstaging (pDS) (RR 6.48, 95% CI 2.05-20.44, p = 0.001) and pathological complete response (RR 18.46, 95% CI 3.34-99.24, p = 0.001); and this was also proven in a subgroup analysis of studies that evaluated pDS in locally advanced UTUC (RR 3.18, 95% CI 2.0-5.07, p < 0.001). The association of NAC with overall survival (OS) and cancer-specific survival (CSS) was also statistically significant in all patients and in patients with locally advanced UTUC. Adjuvant chemotherapy (AC) was associated with improved metastasis-free survival (HR 0.65, 95% CI 0.55-0.76, p < 0.001) and CSS (HR 0.66, 95% CI 0.57-0.77, p < 0.001), which continued to be true for the patients with locally advanced UTUC. The association of AC with OS was only significant in patients with locally advanced UTUC. Perioperative chemotherapy might provide better survival outcomes in patients with clinically non-metastatic UTUC treated with radical nephroureterectomy. Neoadjuvant chemotherapy seems to have promising results, although high level of evidence is still lacking. Despite the low level, the body of evidence suggests a need for multimodal therapy of invasive UTUC.

Department of Special Surgery Jordan University Hospital University of Jordan Amman Jordan

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Department of Urology Jikei University School of Medicine Tokyo Japan

Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology Luzerner Kantonsspital Luzern Switzerland

Department of Urology University Hospital of Tours Tours France

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

European Association of Urology Research Foundation Arnhem The Netherlands

Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Sorbonne Université GRC n°5 ONCOTYPE URO AP HP Urology Hôpital Pitié Salpêtrière 75013 Paris France

See more in PubMed

Margulis V, Shariat SF, Matin SF et al (2009) Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 115:1224 PubMed DOI

Soria F, Shariat SF, Lerner SP et al (2017) Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC). World J Urol 35:379 PubMed DOI PMC

Roupret M, Babjuk M, Comperat E et al (2018) European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2017 update. Eur Urol 73:111 PubMed DOI

Favaretto RL, Shariat SF, Savage C et al (2012) Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma. BJU Int 109:77 PubMed DOI

Janisch F, Shariat SF, Baltzer P et al (2019) Diagnostic performance of multidetector computed tomographic (MDCTU) in upper tract urothelial carcinoma (UTUC): a systematic review and meta-analysis. World J Urol. https://doi.org/10.1007/s00345-019-02875-8 PubMed DOI PMC

Roupret M, Hupertan V, Seisen T et al (2013) Prediction of cancer specific survival after radical nephroureterectomy for upper tract urothelial carcinoma: development of an optimized postoperative nomogram using decision curve analysis. J Urol 189:1662 PubMed DOI

Remzi M, Haitel A, Margulis V et al (2009) Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int 103:307 PubMed DOI

Ploussard G, Xylinas E, Lotan Y et al (2015) Conditional survival after radical nephroureterectomy for upper tract carcinoma. Eur Urol 67:803 PubMed DOI

Robinson BD, Vlachostergios PJ, Bhinder B et al (2019) Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun 10:2977 PubMed DOI PMC

Rink M, Ehdaie B, Cha EK et al (2012) Stage-specific impact of tumor location on oncologic outcomes in patients with upper and lower tract urothelial carcinoma following radical surgery. Eur Urol 62:677 PubMed DOI

Green DA, Rink M, Xylinas E et al (2013) Urothelial carcinoma of the bladder and the upper tract: disparate twins. J Urol 189:1214 PubMed DOI

Audenet F, Isharwal S, Cha EK et al (2019) Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin Cancer Res 25:967 PubMed DOI

Birtle A, Johnson MS, Chester J et al (2020) Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. https://doi.org/10.1016/S0140-6736(20)30415-3 PubMed DOI PMC

Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700 PubMed DOI PMC

Kubota Y, Hatakeyama S, Tanaka T et al (2017) Oncological outcomes of neoadjuvant chemotherapy in patients with locally advanced upper tract urothelial carcinoma: a multicenter study. Oncotarget 8:101500 PubMed DOI PMC

Kobayashi K, Saito T, Kitamura Y et al (2016) Effect of preoperative chemotherapy on survival of patients with upper urinary tract urothelial carcinoma clinically involving regional lymph nodes. Int J Urol 23:153 PubMed DOI

Almassi N, Gao T, Lee B et al (2018) Impact of neoadjuvant chemotherapy on pathologic response in patients with upper tract urothelial carcinoma undergoing extirpative surgery. Clin Genitourin Cancer 16:e1237 PubMed DOI

Kitamura H, Igarashi M, Tanaka T et al (2012) A role for preoperative systemic chemotherapy in node-positive upper tract urothelial carcinoma treated with radical nephroureterectomy. Jpn J Clin Oncol 42:1192 PubMed DOI

Youssef RF, Shariat SF, Lotan Y et al (2011) Upper urinary tract urothelial carcinoma with loco-regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma Collaboration. BJU Int 108:1286 PubMed DOI

Porten S, Siefker-Radtke AO, Xiao L et al (2014) Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer 120:1794 PubMed DOI PMC

Hosogoe S, Hatakeyama S, Kusaka A et al (2018) Platinum-based neoadjuvant chemotherapy improves oncological outcomes in patients with locally advanced upper tract urothelial carcinoma. Eur Urol Focus 4:946 PubMed DOI

Chakiryan N, Martinez A, Gao L et al (2019) Optimizing the sequence of chemotherapy for upper tract urothelial carcinoma with clinically positive regional lymph nodes. J Urol 202:76 PubMed DOI

Huang YC, Chen MF, Shi CS et al (2015) The efficacy of postoperative adjuvant chemotherapy for patients with pT3N0M0 upper tract urothelial carcinoma. J Urol 194:323 PubMed DOI

Song W, Jeong JY, Jeon HG et al (2019) Impact of adjuvant chemotherapy on oncologic outcomes following radical nephroureterectomy for patients with pT3NanyM0 upper tract urothelial carcinoma: a retrospective cohort study. Int J Surg 66:12 PubMed DOI

Fujita K, Inamoto T, Yamamoto Y et al (2015) Role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma and the prognostic significance of C-reactive protein: a multi-institutional, retrospective study. Int J Urol 22:1006 PubMed DOI

Nakagawa T, Komemushi Y, Kawai T et al (2017) Efficacy of post-nephroureterectomy cisplatin-based adjuvant chemotherapy for locally advanced upper tract urothelial carcinoma: a multi-institutional retrospective study. World J Urol 35:1569 PubMed DOI

Ikeda M, Matsumoto K, Hirayama T et al (2018) Selected high-risk patients with upper tract urothelial carcinoma treated with radical nephroureterectomy for adjuvant chemotherapy: a multi-institutional retrospective study. Clin Genitourin Cancer 16:e669 PubMed DOI

Kwak C, Lee SE, Jeong IG et al (2006) Adjuvant systemic chemotherapy in the treatment of patients with invasive transitional cell carcinoma of the upper urinary tract. Urology 68:53 PubMed DOI

Lee KS, Kim KH, Yoon YE et al (2015) Impact of adjuvant chemotherapy in patients with upper tract urothelial carcinoma and lymphovascular invasion after radical nephroureterectomy. Korean J Urol 56:41 PubMed DOI PMC

Seisen T, Krasnow RE, Bellmunt J et al (2017) Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma. J Clin Oncol 35:852 PubMed DOI

Kim HS, Lee JS, Jeong CW et al (2015) Adjuvant chemotherapy for locally advanced upper tract urothelial carcinoma: updated results of the Seoul National University Hospital experience. Int Braz J Urol 41:1067 PubMed DOI PMC

Soga N, Arima K, Sugimura Y (2008) Adjuvant methotrexate, vinblastine, adriamycin, and cisplatin chemotherapy has potential to prevent recurrence of bladder tumors after surgical removal of upper urinary tract transitional cell carcinoma. Int J Urol 15:800 PubMed DOI

Hellenthal NJ, Shariat SF, Margulis V et al (2009) Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration. J Urol 182:900 PubMed DOI

Yafi FA, Tanguay S, Rendon R et al (2014) Adjuvant chemotherapy for upper-tract urothelial carcinoma treated with nephroureterectomy: assessment of adequate renal function and influence on outcome. Urol Oncol 32:31 e17 DOI

Necchi A, Lo Vullo S, Mariani L et al (2018) Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration. BJU Int 121:252 PubMed DOI

Fujita K, Taneishi K, Inamoto T et al (2017) Adjuvant chemotherapy improves survival of patients with high-risk upper urinary tract urothelial carcinoma: a propensity score-matched analysis. BMC Urol 17:110 PubMed DOI PMC

Lucca I, Kassouf W, Kapoor A et al (2015) The role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma following radical nephroureterectomy: a retrospective study. BJU Int 116:72 PubMed DOI

Kim TS, Oh JH, Rhew HY (2013) The efficacy of adjuvant chemotherapy for locally advanced upper tract urothelial cell carcinoma. J Cancer 4:686 PubMed DOI PMC

Leow JJ, Martin-Doyle W, Fay AP et al (2014) A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol 66:529 PubMed DOI

Yang X, Li P, Deng X et al (2017) Perioperative treatments for resected upper tract urothelial carcinoma: a network meta-analysis. Oncotarget 8:3568 PubMed DOI

Martini A, Daza J, Poltiyelova E et al (2019) Pathological downstaging as a novel endpoint for the development of neoadjuvant chemotherapy for upper tract urothelial carcinoma. BJU Int. https://doi.org/10.1111/bju.14719 PubMed DOI

Matin SF, Margulis V, Kamat A et al (2010) Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer 116:3127 PubMed DOI

Favaretto RL, Shariat SF, Chade DC et al (2010) The effect of tumor location on prognosis in patients treated with radical nephroureterectomy at Memorial Sloan-Kettering Cancer Center. Eur Urol 58:574 PubMed DOI PMC

Zargar H, Espiritu PN, Fairey AS et al (2015) Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 67:241 PubMed DOI

Rouprêt M, Babjuk M, Burger M et al (2019) European association of urology guidelines on upper urinary tract urothelial carcinoma. EAU Guidelines Office, Arnhem. ISBN 978-94-92671-04-2

Shirotake S, Kikuchi E, Tanaka N et al (2015) Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma: a Japanese multi-institution experience. J Urol 193:1122 PubMed DOI

Kawashima A, Nakai Y, Nakayama M et al (2012) The result of adjuvant chemotherapy for localized pT3 upper urinary tract carcinoma in a multi-institutional study. World J Urol 30:701 PubMed DOI

Sun M, Bianchi M, Hansen J et al (2012) Chronic kidney disease after nephrectomy in patients with small renal masses: a retrospective observational analysis. Eur Urol 62:696 PubMed DOI

Xylinas E, Rink M, Margulis V et al (2013) Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy. BJU Int 112:453 PubMed DOI

Hassler MR, Abufaraj M, Kimura S et al (2019) Impact of patients’ gender on efficacy of immunotherapy in patients with metastatic kidney cancer: a systematic review and meta-analysis. Clin Genitourin Cancer. https://doi.org/10.1016/j.clgc.2019.09.004 PubMed DOI

Pignot G, Loriot Y, Kamat AM et al (2019) Effect of immunotherapy on local treatment of genitourinary malignancies. Eur Urol Oncol 2:355 PubMed DOI

Update on systemic treatment of upper tract urothelial carcinoma: a narrative review of the literature

Prognostic role of the systemic immune-inflammation index in upper tract urothelial carcinoma treated with radical nephroureterectomy: results from a large multicenter international collaboration

Pre-therapy serum albumin-to-globulin ratio in patients treated with neoadjuvant chemotherapy and radical nephroureterectomy for upper tract urothelial carcinoma

Diagnostic challenges and treatment strategies in the management of upper-tract urothelial carcinoma