Li et al. BMC Urology (2020) 20:97 https://doi.org/10.1186/s12894-020-00610-9 RESEARCH ARTICLE Open Access Intravesical gemcitabine versus mitomycin for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized controlled trial Rongxin Li1†,YeLi1†, Jun Song1,2†, Ke Gao1, Kangning Chen1, Xiaogang Yang1, Yongqiang Ding1, Xinlong Ma1, Yang Wang1, Weipeng Li1, Yanan Wang1, Zhiping Wang1 and Zhilong Dong1* Abstract Background: Mitomycin (MMC) has been frequently used as the compound for intravesical treatment. The relatively new pyrimidine analog gemcitabine (GEM) has exhibited anticancer effect on various solid cancers, such as the advanced bladder cancer. In this study, the GEM and MMC in treating non-muscle invasive bladder cancer (NMIBC) cases was compared through systemic review. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, the electronic databases, including Embase, PubMed, Chinese biomedicine literature database, the Cochrane Library, the National Institute for Health and Clinical Excellence, NHS Evidence, Chinese technological periodical full-text database, and Chinese periodical full-text database, were systemically reviewed from inception to October 2018. Then, the RevMan 5.0 software was applied for data analysis. Five randomized controlled trials (RCTs) involving a total of 335 patients were included. Results: For MMC group, the recurrence rate in the mitomycin arm increased compared with that in GEM group (OR = 0.44 95% CI [0.24, 0.78]), and the difference was statistically significant between the two groups. GEM was associated with reduced incidence of chemical cystitis compared with that of MMC (OR = 0.23 95% CI [0.12, 0.44]). Differences in hematuria (OR = 0.46 95% CI [0.16, 1.31]), skin reaction (OR = 0.49 95% CI [0.14, 1.70]) and liver and kidney function damage (OR = 0.51 95% CI [0.09, 2.85]) displayed no statistical significance between the two groups. Conclusion: Findings in our study demonstrate the superior efficacy of GEM over MMC in reducing the relapse rate among NMIBC patients following transurethral resection (TUR). In addition, GEM is associated with reduced local toxic effects on the bladder compared with those of MMC. However, more future studies are needed to examine GEM safety when used as the monotherapy or polytherapy for bladder patients. More RCTs with high quality are also required to validate our findings due to the limitations of the current meta-analysis. Keywords: Bladder cancer, Gemcitabine, Mitomycin, Systematic evaluation, Meta-analysis * Correspondence: [email protected] †Rongxin Li, Ye Li and Jun Song made equal contribution to this manuscript and should be regarded as co-first authors. 1Lanzhou University Second Hospital, Lanzhou City, Gansu Province, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li et al. BMC Urology (2020) 20:97 Page 2 of 8 Background interfering with DNA repair [11]. On the other hand, Bladder cancer has become a common cancer world- MMC can be triggered within cancer cells through wide, and 430,000 new cases and over 165,000 deaths forming the reducing equivalents, thereby affecting can- are reported in 2012 [1]. Transitional cell carcinoma is cer cell replication through forming the damage-induced dominant in bladder cancer, in addition, adenocarcin- DNA adducts [12]. Nonetheless, it remains unclear oma (cancer originating from the mucus-making and re- about the efficacy and side effects between the two leasing cells) and squamous cell carcinoma (cancer agents. In this regard, the current systematic review was originating from the thin and flat cells) are also observed carried out aiming to evaluate the therapeutic effects [2]. Generally, bladder cancer is associated with the fol- and safety between GEM versus MMC on treating lowing symptoms, frequent urination, bloody urine (ren- NMIBC patients. dering the slight rusty to deep red color of urine), urination pain, or urination sensation with no urine in- Methods deed [3]. Search strategy The incidences of bladder cancer in male and female In accordance with Preferred Reporting Items for Sys- are reported to be 3.4 and 1.2%, respectively, however, tematic Reviews and Meta-Analyses (PRISMA) state- that in patients aged over 70 years is twice to thrice ment [13], the electronic databases, including Embase, higher than that among patients aged 55–65 years, and PubMed, Chinese biomedicine literature database, the 15 to 20 times greater than for patients aged 30–54 years Cochrane Library, the National Institute for Health and [4]. As estimated by the World Health Organization, Clinical Excellence, NHS Evidence, Chinese periodical there were 132,432 bladder cancer-related deaths in the full-text database, and Chinese technological periodical world in 2000 [5]. full-text database, were systemically reviewed from in- About 80% bladder cancers are non-muscle invasive ception to October 2018 to identify the randomized con- bladder cancers (NMIBC) restricted to the urothelium trolled trials (RCTs) that compared the efficacy and (clinical stage Ta) or lamina propria (stage T1) at safety of GEM and MMC in treating NMIBC cases. first, which is featured by the in-situ flat carcinoma Additionally, the critical Chinese magazines in relevant (stage Tis) [6]. Tumor relapse following transurethral fields were also retrieved manually, corresponding search resection (TUR) has been identified as a main issue engines were employed to identify the relevant refer- in treating non-muscle invasive bladder cancer. ences, and each reference in the enrolled articles was re- Specifically, the mechanisms regarding NMIBC relapse trieved as well to discover other possible relevant following TUR are shown as follows, (1) residual publications. Related terms were used for study retrieval. tumor originated from the incomplete resection; (2) Moreover, the reference lists from those enrolled articles floating cancer cell implantation in traumatized blad- and reviews were also manually retrieved, and experts in der sites; (3) incidence of new neoplasm due to high this field were contacted if necessary, while those non- cancer aggressiveness; (4) relapses at the urothelial in- published articles were not found. The study retrieval stability sites (atypia, hyperplasia and dysplasia) [7]; was not restricted by language. (5) over 50–70% tumor relapse since no adjuvant In this study, the following search terms were used in treatment is given, and approximately 15% cases de- retrieval strategy, including intravesical pharmacother- velop muscle-invasive cancers eventually [8]. apy, non-muscle invasive bladder cancer, gemcitabine The intravesical chemotherapy has been considered as and mitomycin, so as to find out the titles and abstracts the standard treatment for patients receiving following of relevant studies. To be specific, the entire retrieval TUR to eradicate underlying disorders, inhibit cancer re- strategy adopted in the current work for the PubMed lapse, prevent tumor development and extend patient database included (irrigation of bladder OR intravesical survival [9]. Mitomycin (MMC) is a frequently used therapy OR bladder instillation OR intravesical instilla- compound in intravesical treatment. In addition, gemci- tion OR intravesical infusion OR infusion of bladder) tabine (GEM), the relatively new pyrimidine analog, dis- AND (non-muscle-invasive bladder cancer OR NMIBC plays anticancer effect on various solid cancers, such as OR non-muscle invasive bladder cancer OR superficial the advanced bladder cancer [10]. MMC and GEM have bladder cancer) AND (GEM OR gemcitabine) AND been classically used as the cytotoxic agents for affecting (MMC OR mitomycin OR mitomycin-c). the DNA integrity, but these two display distinctly differ- ent mechanisms of action. Among them, GEM, the Data collection difluoro-2, 2-deoxy-cytidine, can be activated upon the Two researchers independently reviewed those retrieved stimulation of deoxycytidine kinase, meanwhile, its phos- titles and abstracts in accordance with the study inclu- phorylated metabolites may impact the synthesis of sion criteria, and the inappropriate articles were ex- deoxy-nucleotide through resulting in DNA injuries and cluded. Any disagreement between them was settled Li et al. BMC Urology (2020) 20:97 Page 3 of 8 down through the opinion from a third author. After- analysis. The descriptive approaches