2.1

Search strategy

This systematic review was conducted in line with the updated Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [ ]. The protocol was registered in the International Prospective Register of Ongoing Systematic Reviews (PROSPERO) database (Registration Number CRD42024523231). The PRISMA checklist is provided in eTable 1 , Supplementary Materials. We systematically reviewed the English-language literature using the PubMed/Medline, Web Of Science, and Embase databases to identify reports published from inception to March 2024, which assessed the impact of post-RNU intravesical chemotherapy on intravesical recurrence. A detailed overview of the search strategy is available in eAppendix 1, Supplementary Materials .

2.2

Study selection and inclusion criteria

The primary outcome was post-RNU intravesical recurrence at 12 and 24 months. To address our clinical question, we applied the PICOS framework. We included studies that assessed patients who underwent RNU for UTUC (Patients) and received post-RNU intravesical instillation (Intervention). These patients were compared with those who either did not receive intravesical instillations or were treated with different therapeutic regimens in terms of the agent used, timing relative to the RNU, the number of instillations, or the dosage (Comparator) to assess intravesical recurrence (Outcome) in both prospective and retrospective studies (Study design). The secondary outcomes were to evaluate the overall, minor and major complication rates based on the Clavien-Dindo classification. Initial screening was performed independently by 2 investigators (S.M. and A.P.) based on the titles and abstracts of the articles to identify ineligible reports. Reviews, meta-analyses, editorials, commentaries, authors’ replies, meeting abstracts of unpublished studies, and case reports were excluded, but the reference section was checked to avoid omitting relevant articles. Potentially relevant studies were subjected to a full-text review, and the relevance of the reports was confirmed after the data extraction process. Duplicated studies from the same author’s group were excluded, retaining the ones fulfilling the selection criteria and the most recent ones; however, if they fulfilled the selection criteria and provided additional information on outcomes of interest, they were retained for these outcomes only. However, if the findings were concordant, we extracted and synthesized only the most recent report of that database, fitting all selection criteria. Disagreements were resolved by consultation with a third co-author (A.U.).

2.3

Data extraction

Data on studies, patients, and treatment characteristics were independently extracted by 2 authors (S.M. and A.P.). The following variables were extracted from the included studies: first author’s name, publication year, country and continent of research, study design, number of centers involved, number of patients enrolled, recruitment period, inclusion and exclusion criteria, history of bladder cancer (BCa), surgical approach (open, laparoscopic and robotic), type of bladder cuff excision, tumor characteristics (tumor location and multifocality, stage, tumor size, and grade), information of intravesical chemotherapy (molecule used, timing, and treatment duration), intravesical recurrence rate, and minor and major complication rates.

2.4

Risk of bias (RoB) assessment

Two authors (S.M. and A.P.) independently evaluated the study quality of nonrandomized studies with the ROBINS-I tool [ ]. We judged each bias domain and overall risk of bias as “Low,” “Moderate,” “Serious,” or “Critical” RoB. For Randomized Controlled Studies (RCTs), we used the ROBINS-II tool [ ]. The RoB level was judged as ‘‘low’’, ‘‘some concerns, or ‘‘high’’ risk. For prospective and retrospective single-arm studies, RoB was evaluated according to European Association of Urology guidelines for systematic reviews of case series [ ]. The RoB level, in this case, was judged as ‘‘low’’ or ‘‘high’’ risk. The possible confounders were considered by consensus of 2 authors from a literature review. Disagreements were resolved by consultation with a third co-author (A.U.).

2.5

Statistical analysis

We undertook an initial descriptive analysis of the studies and a pooled analysis evaluating the intravesical recurrence rates in different intravesical chemotherapy settings. The pooled rates represent the average from multiple studies weighted by the inverse of their sampling variances. We performed a meta-analysis to evaluate the intravesical recurrence rates, comparing groups with and without intravesical chemotherapy. Sub-analyses included comparisons between single and multiple intravesical chemotherapy treatments, as well as between intraoperative and postoperative intravesical chemotherapy. We performed a meta-analysis if at least 2 references provided data on an outcome. The Mantel-Haenszel method with odds ratios (ORs) and the corresponding confidence intervals (CIs) were used to determine the association between intravesical recurrence rates and different intravesical chemotherapy schemes. We used dichotomous data to calculate pooled ORs and corresponding 95% CIs. We used a random-effect model to calculate ORs due to the a priori risk of heterogeneity between the included studies. We assessed heterogeneity using the Cochrane’s Q test and quantified it using I ² values. In the case of significant heterogeneity (Cochrane’s Q test P < 0.05), we attempted to investigate and explain the heterogeneity by sensitivity analyses [ ]. All statistical analyses were performed using Cochrane Collaboration Review Manager software (RevMan v.5.4; Cochrane Collaboration, Oxford, UK) and OpenMetaAnalyst software. Statistical significance was set at P < 0.05.

3.1

Study selection and characteristics

We summarized the study selection process in the PRISMA flowchart ( Fig. 1 ). A total of 1,105 records were identified. Of these, 47 full-text articles were assessed for eligibility, and 18 studies met our inclusion criteria [ , , , ]. Four studies were RCTs, twelve were nRCTs, and 2 were single-arm case series. The included studies were published between 2001 and 2024, and most were conducted using a retrospective design (14/18; 78%). In the Supplementary materials ( Appendix 2 ), we provided a complete description of the reasons for exclusion after full-text review. The qualitative and quantitative analysis involved 2,483 patients. Among them, 947 (38%) patients did not receive intravesical chemotherapy after RNU for UTUC. Of the patients who received intravesical chemotherapy, 1226 (49%) were treated with a single instillation and 310 (12%) with multiple instillations. Specifically, 250 (20%) patients received a single intraoperative instillation, 246 (20%) within 48 hours postsurgery, and 738 (60%) after 48 hours. Ten studies involved patients treated with MMC (459 patients), 8 with Epirubicin (881 patients), 2 with Gemcitabine (60 patients), and 2 with Pirarubicin (136 patients).

PRISMA flow diagram.

Eleven (61%) studies exclusively included patients with no prior history of bladder cancer (BCa), while 7 (39%) encompassed both patients with and without a history of BCa. Notably, two of these studies provided intravesical recurrence rates for both cohorts.

Table 1 shows the chemotherapeutic agents used and the timing of administration relative to RNU surgery, as well as the number of instillations and the rate of intravesical recurrence. A detailed description of the patients and tumor characteristics is provided in the Supplementary eTable 5 .

Table 1

Study characteristics and patient demographics in bladder cancer research.

Study, year	Study period	Country	Study design	IVC scheme	Surgical technique	N° of patients (IVC/no-IVC)	Stage ≥ 2	HG	Multifocality	Previous BCa	Follow up (months)
Sakamoto, 2001	1993–1996	Japan	RCT	28 mg MMC+ 200 mg AraC (28 times over 2 yrs) vs. no-IVC	NR	25 (13/12)	0%	NR	16%	0%	45.0 (6.0–65.0)
O’Brien, 2011	2000–2006	UK	RCT	Single MMC 40 mg in 40 ml prior to removal of catheter vs. no-IVC	Open/VLS RNU with ‘‘rip and pluck’’ of the intravesical ureter	239 (120/119)	39%	8%	13%	0%	12.0 (NR)
Ito, 2013	2005–2008	Japan	RCT	Single THP 30 mg for 30 min within 48 hrs after RNU vs. no-IVC	Open/VLS RNU + bladder cuff excision	72 (36/36)	46%	45%	NR	0%	24.9 (2.6–39.3)
Harraz, 2019	2015–2017	Egypt	RCT	Single EPI 50 mg for 30 minutes within 48 hrs vs. EPI 50 mg (6 weekly + monthly 1-yr maintenance)	Open/VLS RNU + bladder cuff excision	74 (38/36)	35%	NR	NR	0%	SIC 18.5 (12.0–38.0) MIC 19.5 (12.0–36.0)
Yamashita, 2017	2012–2013	Japan	Prospective	Single THP 30 mg for 30 min within 48 hrs after RNU vs. no-IVC	Open/VLS RNU + bladder cuff excision	74 (11/63)	59%	NR	NR	0%	24.0 (9.0–45.0)
Abe, 2009	1990–2004	Japan	Retrospective	PEI vs. no-IVC	Open/VLS RNU + bladder cuff excision	59 (21/38)	60%	21%	26%	0%	50.5 (12.0–155.0)
Long, 2017	2004–2012	China	Retrospective	Single postoperative EPI 30 mg for at least 30 min within 1–2 weeks + EPI 30 mg 6–8 times weekly vs. no-IVC	Open RNU + open bladder cuff excision or pluck technique	685 (220/192/273)	64%	NR	25%	NR	47 (36–62)
Huang, 2019	2000–2016	China	Retrospective	Single postoperative EPI 30–50 mg or THP 30–50 mg or MMC 20–40 mg for at least 30 minutes within 2 weeks vs. multiple postoperative IVC (at least 6 weekly doses) vs. no-IVC	Open/VLS RNU + bladder cuff excision	270 (130/99/41)	59%	67%	NR	NR	27.5 (10.8–52.8)
Freifeld, 2020	2012–2018	USA	Retrospective	Intraoperative MMC 20–40 mg or GEM 1–2 g in 50 ml for 60 min (30−120) vs. postoperative IVC	RNU + bladder cuff excision	137 (75/26/36)	34%	69%	13%	30%	8.0 (1.0–55.0)
Fan, 2022	2006–2017	China	Retrospective	Weekly EPI 30 mg in 50 ml vs. no-IVC	RNU + bladder cuff excision	89 (41/48)	78%	74%	23%	0%	29.2 (2.3–122.1)
Said, 2023	2016–2020	USA	Retrospective	Perioperative GEM 2 g for 1 h (after bladder cuff closure) vs. MMC 40 mg or DOX 50 mg (for 1 h, drained before bladder opening)	Robotic RNU + bladder cuff excision	55 (24/NA)	36%	71%	29%	40%	GEM: 11.9 (6.4–20) dIVC:19.6 (12.2–30.5)
Long, 2016	2004–2012	China	Retrospective	Single postoperative EPI (30 mg retained for at least 30 min within 1/2 wks) vs. no-IVC	Open/VLS + bladder cuff excision or pluck technique	320 (161/159)	66%	NR	25%	NR	52.0 (38.0–68.0)
Jiang, 2017	2005–2015	China	Retrospective	Postoperative THP (8 weekly + 6–10 monthly) vs. no-IVC	Open RNU + bladder cuff excision	110 (50/60)	45%	69%	14%	9%	29.0 (2.0–113.0)
Noenning 2018	2008–2016	USA	Retrospective	Intraoperative MMC 40 mg in 40 ml for 30–45 min with drainage prior to bladder cuff removal vs. postoperative (day 1) MMC 40 mg in 40 ml	Open/VLS/robotic RNU + bladder cuff excision	51 (30/21)	37%	69%	NR	37%	I: 22.0 (NR) P: 12.0 (NR)
Gulamhusein, 2020	2017–2019	UK	Retrospective	Postoperative MMC 40 mg in 40 ml within 48 h for 60 min vs. no-IVC	Robotic RNU + bladder cuff excision	69 (69/NA)	NR	55%	NR	41%	13 (2–30)
Nadler, 2021	2017–2020	Denmark	Retrospective	Intraoperative MMC 40 mg in 40 ml for 1 h vs. no-IVC	Robotic RNU + bladder cuff excision	62 (47/15)	29%	18%	NR	37%	16 (9–27)
Wijngaarden, 2023	2007–2021	Netherlands	Retrospective	MMC 40 mg in 50 ml (6 weekly + 5 monthly) starting after 30 days vs. no-IVC	VLS RNU with no sutures in the bladder after cuff excision	66 (39/27)	15%	NR	NR	8%	IVC: 110 (100–120) no-IVC: 48 (33–63)
Lee, 2024	2018–2022	Korea	Retrospective	EPI 50 mg in 50 ml within 48h for 60 min vs. no-IVC	Robotic or open/VLS RNU + bladder cuff excision	167 (51/116)	55%	NR	NR	0%	EPI: 19.6 (16.4–28.7) noIVC:24.8(18.3–34.7)

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