Comparison of Open Versus Laparoscopic Versus Hand-Assisted Laparoscopic Nephroureterectomy: A Systematic Review and Meta-Analysis

Abstract

Background:

A systematic analysis of the evidence regarding oncological, perioperative and postoperative outcomes of open nephroureterectomy (ONU), laparoscopic nephroureterectomy (LNU), and hand-assisted laparoscopic nephroureterectomy (HALNU) was designed.

Methods:

The summarized data were abstracted from 52 original research articles representing 19,195 patients. PubMed/Medline, Scopus, Google Scholar, EMBASE, and the Cochrane Library were reviewed in March 2017, following PRISMA framework. A total of 52 publications were selected for inclusion. The primary outcomes were 2- and 5-year cancer-specific survival (CSS) rate, overall survival (OS) rate, and recurrence-free survival (RFS) rate. The secondary outcomes were operative time, lengths of hospitalization period, estimated blood loss, transfusions, major Clavien complication rate, metastasis rate, bladder recurrence rate, and positive surgical margin.

Results:

On comparing LNU versus ONU and HALNU versus ONU, no significant differences between the 5-year CSS rate (P = .25, P = .39), OS rate (P = .06, P = .46), and RFS rate (P = .85, P = .73) were found. On comparing LNU versus ONU and HALNU versus ONU during a 2-year follow-up period, the following were found: CSS rate (P = .61, P = .04) and OS rate (P = .33, P = .19). There were no significant differences between the LNU versus ONU and HALNU versus ONU rates, regarding bladder recurrence (P = .12, P = .85) and metastasis rate (P = .07, P = .27). Significant higher operative time (P = .01, P = .0004), lower length of hospitalization period (P < .001, P < .001), and estimated blood loss (P = .0004, P < .001) were found in comparison to that of LNU versus ONU and HALNU versus ONU.

Conclusion:

Both LNU and HALNU had comparable oncological and better perioperative and postoperative outcomes, when compared with ONU.

Background

The upper tract transitional cell carcinomas (TCC) are uncommon and aggressive tumors that account for only 5% of all the urothelial cancers.¹ Considering its high potential for recurrence and poor prognosis, the assessment of the predictive factors appears to be increasingly significant. The traditional standard treatment of the upper tract TCC is open nephroureterectomy (ONU) with bladder cuff excision. Major surgeries like these are associated with significant morbidity in the form of blood loss and postoperative pain resulting in prolonged hospitalization. To mitigate this, considerable advancement has been made in minimally invasive techniques with a clear focus on reducing these morbidities. Nevertheless, the fundamental goal in the surgical resection of cancer is oncological control and this should not be compromised at the cost of better immediate operative outcomes.

There is an ongoing debate concerning the real improvements for the minimally invasive surgeries over the open approach. In recent years, a number of studies have been published in an attempt to explore this issue.^2–4 Nevertheless, the limitations, such as small sample size and single-center research, have prevented strong conclusions from being drawn. Therefore, this study conducted a systematic literature review and meta-analysis to determine the current position of ONU, hand-assisted laparoscopic nephroureterectomy (HALNU), and laparoscopic nephroureterectomy (LNU).

Methods

A systematic literature review was performed in March 2017 in multiple databases. The study design, search strategy, data abstraction, and excluded studies were determined using Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria (www.prisma-statement.org) (Table 1 and Fig. 1). The items retrieved were restricted to publications in English.

FIG. 1.

Flowchart of study design and included studies.

Table 1.

Study Design

Patients	Patients underwent LNU, HALNU, or ONU for the primary treatment of upper urinary tract transitional carcinoma
Literature search	Keyword search in PubMed, Google Scholar, and Scopus
Databases	PubMed, Ovid, MEDLINE, EMBASE, the Cochrane Controlled Trials Register, HealthSTAR, CINAHL, Google, and Google Scholar
Limits	Only comprehensive articles without time limit
	Humans
	In English
	Reported complications as Clavien classification
Keywords	Upper urinary tract urothelial carcinoma
	Open radical nephroureterectomy
	Laparoscopic nephroureterectomy
	Hand-assisted laparoscopic nephroureterectomy
	LNU, LRNU, ONU, HALNU
Eligibility criteria	Article in full text (no abstracts)
	Unique publication (no duplicate articles)
	Reported each of the interested outcomes: type of publication (retrospective, nonrandomized trial or randomized trial), duration of follow-up, patient characteristics (number, age, and pathological stage), management of the distal ureter (open, endoscopic, and LigaSure), management of lymph nodes, and total intraoperative and perioperative major Clavien complication rates and other outcomes (mean operative time, length of hospital stay, estimated blood loss, blood transfusions, 2- and 5-year CSS rate, 2- and 5-year OS rate; 2- and 5-year RFS rate, bladder recurrence rate, metastasis rate, and positive surgical margin rate)
	Original report as determined from reading the abstract or if necessary the full text
	Outcome reported in a usable form (each surgical approach was reported as a separate cohort, no additional confounding treatments, no missing or unreliable data; could not have >10% difference in values between text and tables)
Exclusion criteria	Duplicate patient population, where some or all of the same patients were included in a different study reporting on the same parameters (prevents double counting)
	Early case experience (prevents bias toward approaches with more experienced surgeons)
Data abstraction	Articles needed to report, which contain each of outcome of interest to be included in the analysis.
	Data were abstracted by 2 individuals into a custom database table, including list of variables. Fifty percent of articles were abstracted by 1 reviewer and other 50% with other one. The data for 50% of the articles was double entered by a second individual, and any discrepancies were resolved through repeated review and discussion before data analysis.
	All primary outcomes were then double checked and any discrepancies resolved. Variables in four types were abstracted from each study: those necessary to determine inclusion and exclusion criteria, surgical approach, baseline patient characteristics, and clinical outcomes
	To use all data as possible, if only median and range were reported in an article, we substituted the median for the mean (if sample size was >25), and the range/4 (for moderately sized samples [15 < n ≤ 70]) or range/6 (for large samples [n > 70]) for the standard deviation
	All studies were reviewed by 2 independent reviewers using the total QASs to assess the methodological quality of the studies that were included. Although the QASs were reported for each study, they were not used to weight the studies in the meta-analysis.
Primary outcomes	Five-year CSS rate
	Five-year OS rate
	Five-year RFS rate
Secondary outcomes	Total intraoperative and perioperative major Clavien complication rates
	Operative time
	Length of hospital stay
	Estimated blood loss
	Blood transfusions
	Two-year CSS rate
	Two-year OS rate
	Two-year RFS rate
	Bladder recurrence rate
	Metastasis rate
	Positive surgical margin rate
Controls for differences in complication reporting	Calculated complication rate based on Clavien classification criteria rather than using author-provided complication rates
Controls for Publication bias	Performed a funnel plot analysis

CSS, cancer-specific survival; HALNU, hand-assisted laparoscopic nephroureterectomy; LNU, laparoscopic nephroureterectomy; ONU, open nephroureterectomy; OS, overall survival; QAS, quality assessments; RFS, recurrence-free survival.

Original research articles reporting on treatment of upper tract TCC were included. The reference lists of review/meta-analysis articles that included articles not already in our database were also reviewed.^3,4 Conference abstracts were not included because they lacked detail and had not undergone rigorous peer review.

To assess the methodological quality of the studies included, they were initially reviewed by 2 independent reviewers using total quality assessment (QAS) (Table 2). Although the QASs were reported for each study, they were not used to weight the studies in the meta-analysis.

Table 2.

Quality Assessment Items and Possible Scores

A. Was the assigned treatment adequately concealed before allocation?

2 = method did not allow disclosure of assignment

1 = small, but possible chance of disclosure of assignment or unclear

0 = quasi-randomized or open list/tables

B. Were the outcomes of participants who withdrew described and included in the analysis (intention-to-treat)?

2 = withdrawals well described and accounted for in analysis

1 = withdrawals described and analysis not possible

0 = no mention, inadequate mention, or obvious differences, and no adjustment

C. Were the outcome assessors blinded to treatment status?

2 = effective action taken to blind assessors

1 = small or moderate chance of unblinding of assessors

0 = not mentioned or not possible

D. Were the treatment and control groups comparable at entry? (likely confounders may be age, partial or total rupture, activity level, and acute or chronic injury)

2 = good comparability of groups, or confounding adjusted for in analysis

1 = confounding small; mentioned, but not adjusted for

0 = large potential for confounding, or not discussed

E. Were the participants blind to assignment status after allocation?

2 = effective action taken to blind participants

1 = small or moderate chance of unblinding of participants

0 = not possible, or not mentioned (unless double blind), or possible, but not done

F. Were the treatment providers blind to assignment status?

2 = effective action taken to blind treatment providers

1 = small or moderate chance of unblinding of treatment providers

0 = not possible, or not mentioned (unless double blind), or possible, but not done

G. Were care programs, other than the trial options, identical?

2 = care programs clearly identical

1 = clear, but trivial differences

0 = not mentioned or clear and important differences in care programs

H. Were the inclusion and exclusion criteria clearly defined?

2 = clearly defined

1 = inadequately defined

0 = not defined

I. Were the interventions clearly defined?

2 = clearly defined interventions are applied with a standardized protocol

1 = clearly defined interventions are applied, but the application protocol is not standardized

0 = intervention and/or application protocol are poorly or not defined

J. Were the outcome measures used clearly defined? (by outcome)

2 = clearly defined

1 = inadequately defined

0 = not defined

K. Were diagnostic tests used in outcome assessment clinically useful? (by outcome)

2 = optimal

1 = adequate

0 = not defined, not adequate

L. Was the surveillance active, and of clinically appropriate duration?

2 = active surveillance and appropriate duration

1 = active surveillance, but inadequate duration

0 = surveillance not active or not defined

The same authors independently extracted the data, which were later jointly reviewed to reach agreement that the data were accurate. If disagreement existed, it was resolved by consensus or consultation with the senior authors. The data collected from all articles regarding treatment groups included the nephroureterectomy approach (open, laparoscopic, and hand-assisted laparoscopic), type of publication (retrospective, nonrandomized trial, or randomized trial), duration of follow-up, patient characteristics (number, age, and pathological stage; Table 3), management of the distal ureter (open, endoscopic, and LigaSure), management of lymph nodes, and total intraoperative and perioperative major Clavien complication rates⁵ and other outcomes (mean operative time, length of hospital stay, estimated blood loss, blood transfusions, 2- and 5-year cancer-specific survival [CSS] rate, 2- and 5-year overall survival [OS] rate, 2- and 5-year recurrence-free survival [RFS] rate, bladder recurrence rate, metastasis rate, and positive surgical margin rate; Table 3).

Table 3.

Included Study That Divided into Two Comparison Groups

Studies	Type of study	Follow-up	Number (LNU vs. ONU)	Age (year)	Tumor stage	Tumor grade	LNU approach	Management of the distal ureter	Management of lymph nodes	Mean operative time (minutes)	Mean hospital stay (days)	Mean estimated blood loss (mL)	Transfusion rate	2-Year CSS rate	2-Year OS rate	2-year RFS rate	5-Year CSS	5-Year OS	5-Year RFS rate	Bladder recurrence rate	Metastasis rate	Major Clavien complication rate	Positive surgical margin	Quality assessment
LNU vs. ONU
Goel et al.²⁷	Retrospective	15.0/19.0	9/5	58.8/55	N/D	N/D	Retroperitoneal	Open	N/D	188.75 (120–270) vs. 184 (170–200)	5.1 (4–7) vs. 9.2 (8–10)	275.0 (100–600) vs. 570 (200–1000)	N/D	N/D	N/D	9/5	N/D	N/D	N/D	N/D	2/0	N/D	0/0	8
Sato et al.²⁸	Retrospective	25/60	30/23	72/70	T1≥: 20T2: 4T3: 11T4: 1vs.T1>: 10T2: 6T3: 7T4: 0	1:62:243:6vs.1:52:143:4	Retroperitoneal hand assisted	Open	Selectively performed	140 (70–200) vs. 60 (45–85)	16 (10–24) vs. 21 (14–25)	76 (10–519) vs. 140 (46–350)	4/2	28/20	N/D	26/20	N/D	N/D	N/D	12/13	4/3	1/0	N/D	9
Izumi et al.²⁹	Retrospective	N/D	46/19	72/71	T1≥: 23T2: 6T3<: 17vs.T1≥: 10T2: 2T3<: 7	1:32:293:14vs.1:12:153:3	Retroperitoneal	N/D	8/11	338 (220–551) vs. 311 (188–545)	N/D	170 (0–2555) vs. 260 (90–1450)	7/2	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	8
Matsumoto et al.³⁰	Retrospective	N/D	60/53	65/65	Ta, Tis, T1, T2: 35T3,4: 25vs.Ta, Tis, T1, T2: 33T3, T4: 20	N/D	Retroperitoneal	Open	29/33	326/283	N/D	244/565	5/5	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	4/0	N/D	7
Ariane et al.³¹	Retrospective	24.5/40.4	150/459	69.5/69.8	Ta, Tis>: 44T1: 31T2: 20T3: 53T4: 2vs.Ta, Tis: 119T1: 113T2: 45T3: 153T4: 29	1:112:413:98vs.1:392:1663:254	Transperitoneal	Mixed	Selectively performed	240 (180–300) vs. 180 (150–240)	8 (6–12) vs. 9 (7–12)	N/D	N/D	N/D	N/D	N/D	136/358	N/D	78/233	N/D	21/97	7/19	N/D	9
Bariol et al.³²	Retrospective	101/96	25/40	69.5/69.4	Ta, Tis>: 10T1: 7T2: 4T3: 3T4: N/Dvs.Ta, Tis>: 21T1: 7T2: 2T3: 9T4: N/D	1:52:63:13vs.1:42:203: 15	Transperitoneal	Open	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	18/33	14 vs. 23	17/19	7/15	0/1	N/D	N/D	8
Blackmur et al.³³	Retrospective	25.8 vs. 57.0	13/13	68 vs. 67.5	Ta: 10T2: 1T3: 2vs.Ta: 10T2: 1T3: 2	1:12:93:3vs.1:12:93:3	Transperitoneal	Mixed	Selectively performed	191 (135–220) vs. 194 (125–390)	7.5 (3–10) vs. 12.3 (5–29)	N/D	N/D	N/D	N/D	N/D	8/9	7 vs. 9	12/13	1/0	N/D	N/D	N/D	9
Capitanio et al.³⁴	Retrospective	30.6/70.7	270/979	70.2/68.3	Ta, Tis: 103T1: 69T2: 35T3: 59T4: 4vs.Ta, Tis: 204T1: 229T2: 202T3: 306T4: 38	N/D	N/D	Mixed	Selectively performed	N/D	N/D	N/D	N/D	N/D	N/D	N/D	232/715	N/D	234/746	N/D	N/D	1/6	N/D	10
Fairey et al.³⁵	Retrospective	24	446 vs. 403	72.4 vs. 70.5	T1≥: 200T2: 66T3: 99T4: 21vs.T1≥: 185T2: 66T3: 89T4: 22	N/D	Retroperitoneal	N/D	Selectively performed	N/D	N/D	N/D	N/D	339 vs. 294	303 vs. 274	147 vs. 173	N/D	N/D	N/D	N/D	N/D	N/D	42 vs. 40	9
Fang et al.³⁶	Retrospective	22.4 vs. 30.8	28 vs. 34	65.1 vs. 64.3	N/D	N/D	Retroperitoneal	Endoscopic	N/D	205.0 (180.0, 240.0) vs. 240.0 (210.0, 290.0)	8.0 (7.0, 8.0) vs. 12.0 (10.0, 13.0)	300.0 (200.0, 500.0) vs. 120.0 (100.0, 200.0)	N/D	N/D	N/D	17 vs. 19	N/D	N/D	N/D	8 vs. 11	11 vs. 15	N/D	N/D	11
Favaretto et al.³⁷	retrospective	23/23	53/109	73/71	Ta, Tis: 26T1:N/DT2: 10T3: 17T4:N/Dvs.Ta, Tis: 56T1:N/DT2: 18T3: 25T4:N/D	N/D	Mixed	mixed	Selectively performed	265 (230–310) vs. 164 (126–210)	3 (3–4) vs. 5 (4–6)	200 (150–300) vs. 250 (200–400)	9 vs. 28	43 vs. 94	N/D	N/D	N/D	38 vs. 73	22 vs. 41	15 vs. 51	N/D	N/D	N/D	10
Fradet et al.¹⁹	Retrospective	40.4	345 vs. 267	N/D	N/D	N/D	Mixed	Mixed	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	100 vs. 62	N/D	N/D	N/D	8
Gill et al.³⁸	Retrospective	11 vs. 34	42 vs. 35	71.6 vs. 64.3	Ta, Tis: 9T1: 17T2: 5T3: 7T4: 2vs.Ta, Tis: 9T1: 11T2: 3T3: 7T4: 1	1:92:103:23vs.1:62:103:16	Retroperitoneal	Endoscopic	Selectively performed	224.8 ± 64.3 vs. 280.2 ± 73.8	2.3 ± 1.6 vs. 6.6 ± 1.9	173.5 ± 54.2 vs. N/D	N/D	34/35 vs. 26/30	33 vs. 21	N/D	N/D	N/D	N/D	8 vs. 11	3 vs. 4	N/D	3 vs. 5	11
Greco et al.³⁹	Retrospective	60 vs. 60	70 vs. 70	66.4 vs. 67.2	Ta, Tis: 13T1: 17T2: 39T3: 1T4:N/Dvs.Ta, Tis: 14T1: 16T2: 37T3: 3T4:N/D	1: 152:473:8vs.1:172:453:8	Transperitoneal	Ligasure	N/D	240 (180–300) vs. 190 (160–220)	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	52 vs. 51	3 vs. 5	N/D	N/D	0 vs. 1	9
Hanna et al.⁴⁰	Retrospective	N/D	754 vs. 3014	70.1 vs. 70	N/D	N/D	Mixed	Mixed	N/D	N/D	4 (3–6) vs. 5 (4–7)	N/D	78 vs. 464	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	9
Hanske et al.⁴¹	Retrospective	1	599 vs. 297	71 vs. 69	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	55 vs. 65	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	8
Hattori et al.⁴²	Retrospective	17 vs. 35	53 vs. 60	67.1 vs. 65.5	Ta: 24T1: 8T2: 5T3: 16vs.Ta: 8T1: 9T2: 15T3: 23	1:72:323:18vs.1:62:313:23	Retroperitoneal	Endoscopy	Most of the patients	258 ± 48 vs. 324 ± 96	N/D	354 ± 900 vs. 665 ± 692	N/D	42 vs. 48	N/D	N/D	N/D	N/D	N/D	20 vs. 24	5 vs. 10	4 vs. 0	N/D	10
Hemal et al.⁴³	Retrospective	53 vs. 57	21 vs. 27	54.3 vs. 57.1	Ta: 3T1: 8T2: 8T3: 2T4:N/Dvs.Ta: 4T1: 9T2: 11T3: 3T4:N/D	1:62:113:4vs.1:82:133:6	Retroperitoneal	Mixed	Most of the patients	219.2 ± 37.2 vs. 156. 2 ± 33.1	4.84 ± 1.2 vs. 6.88 ± 1.4	299.4 ± 54.1 vs. 525.88 ± 61.2	N/D	N/D	18 vs. 23	N/D	20 vs. 25	N/D	19 vs. 24	2 vs. 3	2 vs. 3	0 vs. 2	0 vs. 0	12
Kitamura et al.⁴⁴	Retrospective	60	LNU: 65HALNU: 9ONU: 34	70 (50–88) vs. 65 (53–71) vs. 69 (32–88)	Tis, a: 16T1: 10T2: 11T3: 28vs.Tis, a: 0T1: 2T2: 3T3: 4vs.Tis, a: 3T1: 7T2: 8T3: 16	1:22:333:30vs.1:02:43:5vs.1:12:143:19	LNUvs.HALNUvs.ONU	Mixed	Selectively performed	327 (168–601) vs. 325 (237–390) vs. 286 (130–577)	10 (4–62) vs. 17 (9–24) vs. 14.5 (5–36)	220 (0–2500) vs. 250 (50–880) vs. 475 (100–3670)	N/D	N/D	N/D	N/D	52 vs. 6 vs. 22	N/D	22 vs. 1 vs. 14	23 vs. 8 vs. 8	N/D	N/D	N/D	12
Kim et al.⁸	Retrospective	38.8 vs. 57.6	100 vs. 271	64.1 vs. 64.9	Ta, Tis, T1: 44T2: 22T3: 34vs.Ta, Tis, T1: 118T2: 41T3: 112	N/D	Transperitoneal	Open	Selectively performed	N/D	N/D	N/D	N/D	N/D	N/D	N/D	76 vs. 223	59 vs. 203	N/D	33 vs. 110	N/D	N/D	3 vs. 11	11
Klingler et al.⁴⁵	Retrospective	22.1 vs. 23.1	19 vs. 15	66 vs. 66	T1: 12T2: 2T3: 5vs.T1: 10T2: 2T3: 3	1:102:33:6vs.1:82:23:5	Transperitoneal	Open	Most of the patients	198 ± 59 vs. 220 ± 51	8.1 ± 2.2 vs. 13.3 ± 4.4	282 ± 141 vs. 532 ± 246	N/D	N/D	N/D	N/D	N/D	N/D	N/D	2 vs. 2	N/D	N/D	0 vs. 0	12
Kume et al.¹⁵	Retrospective	34 vs. 55	13 vs. 28	65.3 vs. 65	Ta: 4T1: 3T2: 2T3: 4T4: 0vs.Ta: 9T1: 7T2: 2T3: 9T4: 1	1:02:113:2vs.1:02:213:7	Retroperitoneal	Open	N/D	371.5 ± 90.8 vs. 229.9 ± 46.6	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	9 vs. 10	N/D	N/D	N/D	8
Liu et al.⁴⁶	Retrospective	60	52 vs. 213	60.2 vs. 62.5	T1: 20T2: 10T3/T4: 22vs.T1: 65T2: 46T3/T4: 102	N/D	Retroperitoneal or transperitoneal	Mixed	Selectively performed	N/D	N/D	N/D	N/D	N/D	N/D	N/D	36 vs. 149	29 vs. 129	24 vs. 125	6 vs. 40	13 vs. 71	N/D	N/D	10
Manabe et al.⁴⁷	Retrospective	13.6 vs. 28	58 vs. 166	72 vs. 72	Ta: 12T1: 16T2: 6T3: 24T4: 0vs.Ta: 29T1: 41T2: 16T3: 73T4: 7	1:42:313:23vs.1:152:873:64	Retroperitoneal	Open	Selectively performed	N/D	N/D	N/D	N/D	50 vs. 144	48 vs. 138	44 vs. 135	N/D	N/D	N/D	19 vs. 63	10 vs. 33	N/D	N/D	11
Matsui et al.¹⁴	Prospective	8.8 vs. 23	17 vs. 17	75.1 vs. 71.1	T1≥: 9T2: 2T3: 5vs.T1≥: 8T2: 4T3: 5	1:12:63:10vs.1:02:63:11	Retroperitoneal	Open	Most of the patients	286.8 (197–363) vs. 239.5 (130–402)	2.7 (1–7) vs. 4.2 (2–10)	151.1 (10–1174) vs. 299.6 (34–976)	N/D	N/D	N/D	N/D	N/D	N/D	N/D	5 vs. 4	N/D	N/D	N/D	12
McNeill et al.⁴⁸	Retrospective	32.9 vs. 42.3	25 vs. 42	68 vs. 69.1	N/D	1:52:63:13vs.1:52:203:16	Transperitoneal	Open	N/D	165 vs. 165	9.1 vs. 10.7	N/D	N/D	21 vs. 33	N/D	N/D	N/D	N/D	N/D	7 vs. 18	7 vs. 8	N/D	N/D	11
Meraney and Gill⁴⁹	Retrospective	N/D	14 vs. 14	65.9 vs. 75.9	N/D	N/D	Retroperitoneal	Endoscopy	N/D	195.0 ± 40.1 vs. 245.9 ± 71.8	1.3 ± 0.5 vs. 5.9 ± 1.9	148.2 ± 69.7 vs. 863.6 ± 1194.6	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	10
Miyazaki et al.⁵⁰	Retrospective	39	222 vs. 527	70.1 vs. 69.5	T2: 58T3: 154T4: 10vs.T2: 154T3: 329T4: 44	1:42:723:146vs.1:82:1893:324	Retroperitoneal/transperitoneal	Mixed	Selectively performed	N/D	N/D	N/D	N/D	162 vs. 401	138 vs. 381	N/D	N/D	N/D	N/D	69 vs. 174	75 vs. 186	N/D	N/D	10
Okegawa et al.⁵¹	Prospective	24.3 vs. 29.2	25 vs. 23	64.8 vs. 68.1	Ta,Tis: 4T1: 10T2: 7T3: 4T4: 0vs.Ta,Tis: 1T1: 8T2: 9T3: 4T4: 1	1:22:173: 6vs.1:12:153: 7	Retroperitoneal	Open	Selectively performed	298.7 (198–432) vs. 313.4 (162–562)	11.0 (8–14) vs. 12.8 (8–16)	258.3 (15–2000) vs. 403.2 (120–983)	2 vs. 3	N/D	N/D	N/D	N/D	N/D	N/D	5 vs. 4	2 vs. 3	N/D	N/D	12
Rassweiler et al.¹²	Retrospective	N/D	23 vs. 21	62.2 vs. 70.5	Ta,Tis: 12T1: 4T2: 3T3: 4T4: N/Dvs.Ta,Tis: 3T1: 5T2: 3T3: 8T4: 2	1:12:123:10vs.1:N/D2:83:13	Retroperitoneal/transperitoneal	Open	N/D	N/D	N/D	N/D	N/D	N/D	19 vs. 13	N/D	N/D	20 vs. 17	N/D	8 vs. 3	4 vs. 6	9 vs. 10	N/D	11
Roupret et al.¹	Retrospective	69 vs. 78	20 vs. 26	65.8 vs. 71.1	Ta,Tis: 6T1: 9T2: 2T3: 2T4: 1vs.Ta,Tis: 6T1: 5T2: 5T3: 7T4: 3	N/D	Retroperitoneal	Open	N/D	164.8 (80–280) vs. 155.2 (80–380)	3.7 (3–6) vs. 9.2 (7–12)	274.5 (10–2000) vs. 337.7 (20–1250)	2 vs. 3	N/D	18 vs. 20	N/D	18 vs. 16	N/D	N/D	2 vs. 4	2 vs. 9	N/D	0 vs. 0	12
Simone et al.⁷	Prospective, randomized	41	40 vs. 40	59.6 vs. 61.3	Ta, T1: 20T2: 8T3: 12vs.Ta,T1: 12T2: 15T3: 13	1:62:443:12vs.1:52:443:13	Retroperitoneal	LigaSure	Selectively performed	82 (50–140) vs. 78 (35–150)	2.3 (2–3) vs. 3.65 (3–5)	104 (50–260) vs. 430 (250–760)	0 vs. 0	N/D	N/D	N/D	32 vs. 36	N/D	N/D	10 vs. 9	11 vs. 6	N/D	N/D	14
Stewart et al.⁵²	Retrospective	138 vs. 169	23 vs. 39	67.4 vs. 68.1	Ta: 10T1: 7T2: 3T3: 3vs.Ta: 20T1: 8T2: 2T3: 9	1:32:73:13vs.1:42:203:15	Transperitoneal	Open	Selectively performed	165 (105–480) vs, 180 (90–390)	7 (2–30) vs. 10 (5–29)	280 (50–1145) vs. 398 (100–1700)	N/D	N/D	N/D	N/D	16 vs. 31	14 vs. 25	17 vs. 30	12 vs. 22	7 vs. 5	1 vs. 5	N/D	12
Sugihara et al.⁵³	Retrospective	N/D	2902 vs. 2902	73 vs. 73	T1: 1334T2: 667T3: 830T4: 71vs.T1: 1223T2: 741T3: 866T4: 72	N/D	Retroperitoneal	N/D	N/D	N/D	11 (9–14) vs. 12 (10–17)	N/D	375 vs. 599	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	10
Taweemonkongsap et al.¹¹	Retrospective	26.4 vs. 27.9	31 vs. 29	63.8 vs. 66.8	T1: 16T2: 10T3: 4T4: 1vs.T1: 13T2: 12T3: 4T4:N/D	N/D	Retroperitoneal	Open	Selectively performed	258.87 (90–425) vs. 190.69 (105–360)	9.32 (6–20) vs. 8.69 (5–13)	289.35 (100–800) vs. 313.79 (50–800)	6 vs. 7	26 vs. 26	26 vs. 24	N/D	N/D	N/D	N/D	9 vs. 13	3 vs. 2	N/D	N/D	11
Tsujihata et al.⁵⁴	Retrospective	22.4 vs. 22.1	25 vs. 24	66.6 vs. 68.3	Ta, Tis: 3T1: 9T2: 11T3: 2T4:N/Dvs.Ta, Tis: 6T1: 9T2: 2T3: 4T4:N/D	1:52:153:5vs.1:02:113:12	Retroperitoneal	Open	N/D	305.9 (190–480) vs. 271.2 (135–480)	2.2 (1–3) vs. 4.0 (3–5)	321.5 (80–1370) vs. 557.7 (100–1730)	N/D	N/D	N/D	N/D	N/D	N/D	N/D	7 vs. 8	0 vs. 2	N/D	N/D	10
Waldert et al.¹⁰	Retrospective	41 vs. 41	43 vs. 59	65.56 vs. 68.46	Ta, Tis: 11T1: 9T2: 5T3: 18T4:N/Dvs.Ta, Tis: 13T1: 16T2: 10T3: 20T4:N/D	1:62:193:18vs.1:42:313:24	Retroperitoneal or transperitoneal	Open	Most of the patients	220 (62–280) vs. 212 (70–240)	8.1 (7–9) vs. 13.8 (9–16)	300 (50–800) vs. 542 (80–980)	N/D	N/D	N/D	N/D	36 vs. 47	N/D	N/D	5 vs. 9	N/D	N/D	N/D	11
Walton et al.⁵⁵	Retrospective	17 vs. 36	70 vs. 703	70 vs. 68	Ta, Tis: 19T1: 20T2: 8T3: 19T4: 4vs.Ta, Tis: 153T1: 175T2: 139T3: 196T4: 40	1:112:53:54vs.1:882:2193:396	Transperitoneal	Mixed	Selectively performed	N/D	N/D	N/D	N/D	N/D	N/D	N/D	53 vs. 530	N/D	44 vs. 518	N/D	N/D	N/D	N/D	9
Zou et al.⁵⁶	Retrospective	53	21 vs. 101	63.2 vs. 63.8	T1: 8T2: 10T3: 2T4: 1vs.T1: 40T2: 38T3: 18T4: 5	N/D	Trans peritoneal	Mixed	Most of the patient	N/D	N/D	N/D	N/D	19 vs. 87	N/D	N/D	18 vs. 80	N/D	N/D	N/D	N/D	N/D	1 vs. 2	10
Aguilera et al.⁵⁷	Retrospective	24 vs. 52.7	25 vs. 70	66.7 vs. 67.5	Ta, Tis: 2T1: 17T2: 1T3: 5T4: 0vs.Ta, Tis: 10T1: 36T2: 7T3: 12T4: 5	1:32:143:8vs.1:42:313:35	Transperitoneal	Mixed	Selectively performed	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	2 vs. 11	N/D	N/D	9
Koda et al.¹⁶	Retrospective	16.4 vs. 46.2	79 vs. 27	71.4 vs. 67.4	Ta, Tis: 17T1: 20T2: 11T3: 28T4: 3vs.Ta, Tis: 8T1: 6T2: 6T3: 7T4: 0	1:102:333:36vs.1:32:163:8	Retroperitoneal	Open	Not performed	299.2 (140–637) vs. 350.0 (215–610)	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	22 vs. 9	N/D	N/D	N/D	9
Terakawa et al.⁹	Retrospective	25.2 vs. 33.8	120 vs. 120	68.7 vs. 71.3	Ta, Tis: 34T1: 25T2: 19T3: 40T4: 2vs.Ta, Tis: 24T1: 26T2: 27T3: 43T4: 0	1:82:693:43vs.1:152:573:48	Retroperitoneal	Open	Selectively performed	346.3 ± 113.8 vs. 209.2 ± 95.6	9.9 ± 4.1 vs. 13.4 ± 7.7	358.8 ± 366.8 vs. 434.3 ± 356.6	N/D	N/D	N/D	N/D	N/D	N/D	N/D	43 vs. 43	N/D	N/D	N/D	8
Shalhav et al.⁵⁸	Retrospective	24 vs. 24	25 vs. 17	69.7 vs. 62	N/D	N/D	Transperitoneal	Mixed	N/D	184.8 (105.6–264) vs. 93.6 (50.4–144)	6.1 (2–65) vs. 12 (4–34)	199 (25–400) vs. 441 (150–1000)	N/D	10/13 vs. 10/13	N/D	N/D	N/D	10/13 vs. 9/13	N/D	3/13 vs. 7/13	5/13 vs. 4/13	2 vs. 5	N/D	12
HALNU vs. ONU
Chung et al.²⁴	Retrospective	48 vs. 59.5	39/36	66/70	Ta, Tis: 6T1: 12T2: 9T3: 12vs.Ta, Tis: 3T1: 14T2: 13T3: 6	1:12:223: 16vs.1:12: 203: 15	HALNU	Open	Selectively performed	233 vs. 220	7.4 vs. 9.3	183 vs. 422	11/16	N/D	N/D	N/D	35 vs. 31	32 vs. 26	20 vs. 17	17 vs. 13	6 vs. 4	N/D	N/D	10
Chung et al.²⁵	Retrospective	72 vs. 115	31 vs. 21	69.9 vs. 67.4	T3: 4 vs. T3: 7	1: 92: 153: 7vs.1: 72:103:14	HALNU	Open	Selectively performed	195 ± 490 vs. 200 ± 500	6.6 ± 1.8 vs. 12.6 ± 8.20	113 ± 163 vs. 487 ± 360	N/D	N/D	N/D	N/D	20 vs. 24	16 vs. 19	19 vs. 23	4 vs. 10	1 vs. 5	N/D	N/D	12
Hsueh et al.²⁰	Retrospective	35.1 vs. 16.0	58 vs. 87	N/D	Ta: 4T1: 25T2: 14T3: 14T4: 1vs.Ta: 0T1: 53T2: 18T3: 10T4: 6	N/D	HALNU	Open	N/D	259.1 (75–505) vs. 230.2 (125–535)	9.3 (4–20) vs. 12.6 (7–34)	410 (100–1000) vs. 750 (500–4000)	N/D	N/D	N/D	N/D	N/D	N/D	N/D	5 vs. 8	6 vs. 7	N/D	N/D	10
Hsueh et al.⁵⁹	Retrospective	37.6 vs. 53.6	66 vs. 77	68.8 vs. 68.0	Ta: 2T1: 33T2: 15T3: 15T4: 1vs.Ta: 1T1: 42T2: 17T3: 11T4: 6	1:12:253:38vs.1:32:393:34	HALNU	Open	Selectively performed	N/D	N/D	N/D	N/D	N/D	N/D	51 vs. 56	52/63 vs. 54/70	41/63 vs. 49/70	N/D	N/D	6 vs. 12	N/D	N/D	9
Raman et al.²⁶	Retrospective	31.7 vs. 51	38 vs. 52	71 vs. 72	Ta+Tis+T1: 27T2+T3+T4: 9vs.Ta+Tis+T1: 41T2+T3+T4: 11	N/D	HALNU	Mixed	Selectively performed	244 (90–500) vs. 243 (50–400)	4.6 (2–8) vs. 7.1 (4–13)	191 (25–475) vs. 478 (100–2200)	N/D	37 vs. 43	36 vs. 40	22 vs. 23	N/D	N/D	N/D	18 vs. 11	N/D	N/D	N/D	9
Kawauchi et al.²²	Retrospective	13.1 vs. 48.8	34 vs. 34	67.4	Tis, a: 10T1: 5T2: 7T3: 12 vs.Tis, a: 5T1: 5T2: 11T3: 13	1:52:203:9vs.1:42:173:13	HALNU	Open	N/D	233 (150–470) vs. 236 (120–390)	13 (8–27) vs. 21.1 (11–45)	236 (20–1500) vs. 427 (80–1310)	1 vs. 4	N/D	N/D	N/D	N/D	N/D	30 vs. 18	3 vs. 13	2 vs. 3	2 vs. 0	N/D	11
Seifman et al.⁶⁰	Prospective	17	15 vs. 11	71	Ta,Tis: 11T1: 2T2: 0T3: 3 vs.Ta,Tis: 2T1: 0T2: 4T3: 5	1:32:43:6vs.1:12:43:6	HALNU	Open	N/D	320 ± 56 vs. 199 ± 50	N/D	557 ± 1100 vs. 345 ± 234	2 vs. 2	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	3 vs. 3	N/D	10
Stifelman et al.²³	Retrospective	13 vs. 17	11 vs. 11	N/D	N/D	N/D	HALNU	Open	N/D	291 (220–380) vs. 232 (122–420)	4.6 (3–6) vs. 6.1 (4.75–10)	147 (50–350) vs. 311 (50–750)	0 vs. 0	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	N/D	0 vs. 1	10
Sato et al.²⁸	Retrospective	25 vs. 60	36 vs. 23	72 vs. 70	T1≥: 20T2: 4T3: 11T4: 1 vs.T1≥: 10T2: 6T3: 7T4: 0	1:62:243:6vs.1:52:143:4	HALNU	Open	Selectively performed	140 (70–200) vs. 60 (45–85)	16 (10–24) vs. 21 (14–25)	76 (10–519) vs. 140 (46–350)	4 vs. 2	34 vs. 21	N/D	N/D	N/D	N/D	N/D	12 vs. 13	4 vs. 3	1 vs. 0	N/D	9

CSS, cancer-specific survival; HALNU, hand-assisted laparoscopic nephroureterectomy; LNU, laparoscopic nephroureterectomy; N/D. not determined; ONU, open nephroureterectomy; OS, overall survival; RFS, recurrence-free survival.

The primary and secondary outcome measures were oncologic and perioperative outcomes, respectively. Two measurements on oncologic outcomes were evaluated. We looked at the 5-year RFS rate, 2- and 5-year CSS rates, 2- and 5-year OS rates, recurrence rate, bladder recurrence rate, and metastasis rate. Recurrence was defined as tumor relapse during the follow-up period.

Statistical methods

Review Manager version 5.2 (downloaded from http://community.cochrane.org/tools/review-production-tools/revman-5) was used to analyze the selected studies. Continuous data for each arm of a particular study were expressed as mean and standard deviation (SD). Dichotomous data were expressed as proportions or risks and the treatment effect was reported as odds ratios (OR) with a 95% confidence interval (95% CI). To use all data, if only median and range were reported in an article, the median was substituted for the mean when the sample size was greater than 25 and if the sample size was lower than 25, we used the following formula: a +2(m) + b/4 using the values of the median (m), low and high end of the range (a and b, respectively). The SD can be estimated using the formula as follows, which was discussed in previous study: a − b/4 (for moderately sized samples [15 < n ≤ 70]) or a − b/6 (for large samples [n > 70]).

Heterogeneity between studies was assessed using the chi-squared test and I² statistic. A P value <.1 and an I² value >50% were considered suggestive of statistical heterogeneity, prompting a random effects modeling estimate. A nonsignificant chi-squared test result (P ≥ .1 and I² ≤ 50%) suggested that there was no evidence of heterogeneity and a random-effect model was used. Funnel plots were constructed for the outcomes to assess publication bias, which is defined as the tendency not to publish studies with a negative result. The more asymmetric the funnel plot was, the higher the potential bias was. Statistical significance was set at P < .05.

Results

This systematic review and meta-analysis included 19,195 patients, 11,787 undergoing ONU, 7071 undergoing LNU, and 337 undergoing HALNU. Of the preoperative data, there were significant differences in pathological stages between studies (ONU: Ta, Tis 22.2%, T1 21.9%, T2 16.1%, T3 30.4%, T4 9.4%; LNU: Ta, Tis 28.7%, T1 28.4%, T2 16.0%, T3 25.3%, T4 1.6; and HALNU: Ta, Tis 9.7%%, T1 33.3%, T2 36.0%, T3 20.2%, T4 0.8%; P < .0001).

ONU versus LNU

Five-year CSS rate

There was significant heterogeneity between studies that compared ONU and LNU (I² = 60%; P = .002); thus, random effects were used to analyze the outcome. There was no significant difference in CSS rate after 5 years between ONU and LNU (OR: 1.24; 95% CI: 0.86–1.79; P = .25; Fig. 2).

FIG. 2.

Analysis showed no significant difference in CSS rate after 5 years between ONU and LNU. CSS, cancer-specific survival; LNU, laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

Five-year OS rate

No significant heterogeneity was detected between the studies in this outcome (I² = 1%; P = .42); thus, fixed effects were used to analyze the outcome. There was no significant difference OS rate after 5 years between ONU and LNU (OR: 0.76; 95% CI: 0.57–1.02; P = .06; Fig. 3).

FIG. 3.

Analysis showed no significant difference overall, 5-year recurrence-free, 2-year cancer specific, 2-year overall, and 2-year RFS rate after 5 years between ONU and LNU. LNU, laparoscopic nephroureterectomy; ONU, open nephroureterectomy; RFS, recurrence-free survival.

Five-year RFS rate

There was significant heterogeneity between studies that compared ONU and LNU (I² = 56%; P = .01); thus, random effects were used to analyze the outcome. There was no significant difference in RFS rate after 5 years between ONU and LNU (OR: 1.03; 95% CI: 0.74–1.43; P = .85; Fig. 3).

Two-year CSS rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 0%; P = .46); thus, fixed effects were used to analyze the outcome. There was no significant difference in CSS rate after 2 years between ONU and LNU (OR: 1.05; 95% CI: 0.86–1.29; P = .61; Fig. 3).

Two-year OS rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 41%; P = .11); thus, fixed effects were used to analyze the outcome. There was no significant difference in OS rate after 2 years between ONU and LNU (OR: 0.91; 95% CI: 0.75–1.10; P = .33; Fig. 3).

Two-year RFS rate

There was no significant heterogeneity between studies that compared ONU and LNU (I² = 0%; P = .67); thus, fixed effects were used to analyze the outcome. There was a significantly higher RFS rate after 2 years in ONU compared with LNU (OR: 0.69; 95% CI: 0.54–0.89; P = .004; Fig. 3).

Bladder recurrence rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 0%; P = .49, Fig. 4); with fixed effects analysis, there was no significant difference in intravesical recurrence between ONU and LNU (OR: 0.89; 95% CI: 0.77–1.03; P = .12; Fig. 5).

FIG. 4.

Analysis showed heterogeneity between studies in whom intravesical recurrence was compared between ONU and LNU. LNU, laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

FIG. 5.

Analysis showed no significant difference in metastasis rate between ONU and LNU. LNU, laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

Metastasis rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 0%; P = .63); with fixed effects analysis, there was no significant difference in metastasis rate between ONU and LNU (OR: 0.83; 95% CI: 0.68–1.02; P = .07; Fig. 5).

Major Clavien complication rate

There was no significant heterogeneity between studies that compared ONU and LNU (I² = 0%; P = .25); thus, fixed effects were used to analyze the outcome. There was no significant difference in major Clavien complication rate between ONU and LNU (OR: 0.95; 95% CI: 0.57–1.59; P = .86; Fig. 6).

FIG. 6.

Analysis showed no significant difference in major Clavien complication rate, positive surgical margin between ONU and LNU. LNU, laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

Positive surgical margin

There was no significant heterogeneity between the studies in regard to this outcome (I² = 0%; P = .75); with fixed effects analysis, there was no significant difference in positive surgical margin between ONU and LNU (OR: 0.87; 95% CI: 0.58–1.31; P = .51; Fig. 6).

Mean operative time (minutes)

There was significant heterogeneity between studies that compared ONU and LNU (I² = 98%; P < .0001); thus, random effects were used to analyze the outcome. There was a significantly higher operative time in LNU compared to ONU (mean difference: 26.44; 95% CI: 6.45–46.42; P = .01; Fig. 7).

FIG. 7.

Analysis showed significantly higher operative time, lower length of stay, and lower estimated blood loss and transfusion rate in LNU compared to ONU. LNU, laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

Length of hospital stay (days)

There was significant heterogeneity between studies that compared ONU and LNU (I² = 99%; P < .0001); thus, random effects were used to analyze the outcome. There was a significantly higher length of hospital stay in ONU compared to LNU (mean difference: −2.66; 95% CI: −3.10 to −2.22; P < .001; Fig. 7).

Mean estimated blood loss (mL)

There was significant heterogeneity between studies that compared ONU and LNU (I² = 97%; P < .0001); thus, random effects were used to analyze the outcome. There was a significantly higher estimated blood loss in ONU compared to LNU (mean difference: −136.36; 95% CI: −212.48 to −60.24; P = .0004; Fig. 7).

Transfusion rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 4%; P = .4); with fixed effects analysis, there was a significantly higher rate of blood transfusion in ONU compared to LNU (OR: 0.57; 95% CI: 0.51–0.64; P < .0001; Fig. 7).

ONU versus HALNU

Five-year CSS rate

There was no significant heterogeneity between studies that compared ONU and HALNU (I² = 0%; P = 0.96); thus, fixed effects were used to analyze the outcome. There was no significant difference in CSS rate after 5 years between ONU and HALNU (OR: 1.34; 95% CI: 0.69–2.60; P = .39; Fig. 8).

FIG. 8.

Analysis showed no significant difference in cancer-specific, overall, recurrence-free survival rate after five years between ONU and HALNU. Nevertheless, there was significant difference in CSS rate after 2 years between ONU and HALNU. CSS, cancer-specific survival; HALNU, hand-assisted laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

Five-year OS rate

There was significant heterogeneity between the studies in this outcome (I² = 74%; P = .02); thus, random effects were used to analyze the outcome. There was no significant difference in OS rate after 5 years between ONU and HALNU (OR: 0.63; 95% CI: 0.18–2.19; P = .46; Fig. 8).

Five-year RFS rate

There was significant heterogeneity between studies that compared ONU and HALNU (I² = 79%; P = .009); thus, random effects were used to analyze the outcome. There was no significant difference in RFS rate after 5 years between ONU and HALNU (OR: 1.35; 95% CI: 0.25–7.34; P = .73; Fig. 8).

Two-year CSS rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 13%; P = .28); thus, fixed effects were used to analyze the outcome. There was a significant difference in CSS rate after 2 years between ONU and HALNU (OR: 4.08; 95% CI: 1.03–16.08; P = .04; Fig. 8).

Two-year RFS rate

There was no significant heterogeneity between studies that compared ONU and HALNU (I² = 0%; P = .60); thus, fixed effects were used to analyze the outcome. There was no significant difference in RFS rate after 2 years between ONU and HALNU (OR: 1.46; 95% CI: 0.83–2.58; P = .19; Fig. 8).

Bladder recurrence rate

There was significant heterogeneity between the studies in regard to this outcome (I² = 81%; P < .0001); with random effects analysis, there was no significant difference in intravesical recurrence between ONU and HALNU (OR: 0.91; 95% CI: 0.32–2.59; P = .85; Fig. 9).

FIG. 9.

Analysis showed no significant difference in intravesical recurrence, metastasis rate between ONU and HALNU. HALNU, hand-assisted laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

Metastasis rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 4%; P = .39); with fixed effects analysis, there was no significant difference in metastasis rate between ONU and HALNU (OR: 0.73; 95% CI: 0.43–1.27; P = .27; Fig. 9).

Major Clavien complication rate

There was no significant heterogeneity between studies that compared ONU and HALNU (I² = 0%; P = .50); thus, fixed effects were used to analyze the outcome. There was no significant difference in major Clavien complication rate between ONU and HALNU (OR: 1.43; 95% CI: 0.38–5.36; P = .59; Fig. 10).

FIG. 10.

Analysis showed no significant difference in major Clavien complication rate between ONU and HALNU. There was significantly higher operative time in HALNU compared to ONU. Nevertheless, there was significant higher length of hospital stay and estimated blood loss in ONU compared to HALNU. HALNU, hand-assisted laparoscopic nephroureterectomy; ONU, open nephroureterectomy.

Mean operative time (minutes)

There was significant heterogeneity between studies that compared ONU and HALNU (I² = 83%; P < .0001); thus, random effects were used to analyze the outcome. There was a significantly higher operative time in HALNU compared to ONU (mean difference: 60.86; 95% CI: 27.30–94.41; P = .0004; Fig. 10).

Length of hospital stay (days)

There was significant heterogeneity between studies that compared ONU and HALNU (I² = 67%; P < .006); thus, random effects were used to analyze the outcome. There was a significantly higher length of hospital stay in ONU compared to HALNU (mean difference: −3.34; 95% CI: −4.49 to −2.19; P < .001; Fig. 10).

Mean estimated blood loss (mL)

There was significant heterogeneity between studies that compared ONU and HALNU (I² = 71%; P = .0009); thus, random effects were used to analyze the outcome. There was a significantly higher estimated blood loss in ONU compared to HALNU (mean difference: −215.64; 95% CI: −314.39 to −116.90; P < .0001; Fig. 10).

Transfusion rate

There was no significant heterogeneity between the studies in regard to this outcome (I² = 0%; P = .66); with fixed effects analysis, there was no significant difference in rate of blood transfusion in ONU compared to HALNU (OR: 0.55; 95% CI: 0.27–1.13; P = .10; Fig. 10).

Discussion

This study is the largest compilation of comprehensive studies on nephroureterectomy patients till date. It is a systematic review and meta-analysis of this large body of literature. Due to the lack of randomized clinical trials, the differences in the patient characteristics between the surgical cohorts could explain the differences in the outcomes between the treatment groups. These differences cannot be fully corrected by statistical methods. In addition, unknown differences in the attributes of the patients and physicians and/or the treatments administered could contribute to the heterogeneous outcomes between the studies. Caution is advised when interpreting the findings of this meta-analysis within the context of the aforementioned considerations. The large number of patients included in the meta-analysis means that the statistically significant results may not necessarily be clinically meaningful.

Open radical nephroureterectomy has been the standard treatment for several decades. Nowadays, to minimize the morbidities, LNU is an appealing option and choosing LNU for treatment of upper urinary tract TCC is rapidly growing, as Inman⁶ said, “the horse was already out of the barn.” Nevertheless, most of the studies that compare ONU with LNU are low in quality and consist of only one randomized clinical trial.⁷ They have been designed to answer the question of which surgical approach is appropriate.

Regarding the survival outcomes, there is great discrepancy between the studies. Kim et al.⁸ performed subgroup analyses by stratifying the study cohort by pathological tumor stages and showed that the LNU group had worse 5-year OS and CSS rates than the ONU group in only the pT3/T4 patients compared with the other stage patients. Moreover, they postulated that the LNU is an independent predictor of OS and CSS rates than ONU. In contrast, Terakawa et al.⁹ showed that laparoscopic approach had no independent prognostic impact on the outcomes of the patients. Simone et al.,⁷ in a randomized prospective study, postulated that the CSS rate and the metastasis free survival rate were significantly in favor of the ONU than the LNU after matching for pT3 and high-grade tumors. These findings highlight the importance of careful selection of the surgical procedure (open or laparoscopic). Nevertheless, the small sample size, single-center experience, and the personal choice of laparoscopic technique could make the bias in the outcomes, especially when the sample size in Simone et al., study⁷ was defined based on the mean time of discharge. Also, the oncologic outcomes have to be considered preliminary.

In most of the previous studies,^10–12 no significant differences were found regarding the oncologic outcomes between the LNU and ONU. Our analysis found that the LNU had similar or better oncologic efficacy than the ONU. Other reasons for those inconsistent results could be explained as follows: owing to the retrospective nature of the studies, it is likely that there may be some inherent bias. In some studies, the surgical cases spanned multiple years with multiple surgeons, which resulted in the variation in surgical expertise and learning curve for laparoscopic surgery among surgeons, which could not be clearly identified in their studies, besides these factors perhaps being responsible for affecting the survival outcomes after the LNU. Also, given that most patients did not receive pelvic lymph node dissection in the studies, which is considered an important part in the current management of the upper urinary tract TCC. More importantly, all the oncologic outcomes should have been compared by pathologic stage and grade as preplanned. Unfortunately, such analyses could not be achieved due to insufficient data. In addition, the inclusion of patients with a prior or concomitant history of bladder cancer may affect the oncologic outcome of treating upper tract TCC; besides, this factor is not similar between the studies. Therefore, further studies with larger cohorts of patients and long follow-up will be able to provide a conclusive data.

Regarding the bladder recurrence, Xylinas et al.¹³ showed that the laparoscopic approach was associated with a higher risk of intravesical recurrence than open surgery. It was suggested that the high-pressure pneumoperitoneum during LNU might trigger tumor dissemination and could result in a higher rate of recurrence. Some authors^14,15 drew a similar conclusion, whereas others did not confirm these results.^16,17 Our finding showed no significant difference in the rate of bladder recurrence between LNU and ONU. A recently published review described multifocality as the only repeatedly mentioned significant risk factor for bladder cancer recurrence after upper urinary tract TCC.¹⁸ Nevertheless, Fradet et al.¹⁹ showed that the age of every patient at diagnosis raises the risk of developing subsequent bladder cancer by 2.8% and reported tumor location in both the renal pelvis and the ureter. Treating with adjuvant systemic chemotherapy, extravesical ureterectomy and LNU were the factors with higher rate of bladder recurrence after nephroureterectomy. The question might arise whether probably other co-factors, such as distal ureter management, could be responsible for these discrepancies between the results. The patients subjected to LNU were more likely to undergo open bladder cuff excision or the transurethral resection of the orifice. Thus, we would expect a selection bias affecting the outcomes against ONU.

In our analysis, intraoperative and postoperative outcomes were found similar to the previous findings that exhibited a higher operative time, lower length of hospital stay, lower estimated blood loss, and a need to transfusion rate in LNU versus ONU.

On the comparison of HALNU with ONU, we found that the oncologic outcomes were comparable between the two approaches. Several reports have evaluated the short-term oncologic outcomes of HALNU in treating upper urinary tract TCC.^20–23 Chung et al. in 2007²⁴ and 2009²⁵ compared these two approaches and showed that the oncologic outcomes were comparable between the two groups. Also, they found better perioperative outcomes and lower length of hospital stay in the case of HALNU. Raman et al.²⁶ compared the 38 patients who underwent HALNU with the 52 patients who underwent ONU. They showed that HALNU is an effective modality for the treatment of the upper urinary tract urothelial carcinoma. Patients benefited from less intraoperative blood loss and a shorter hospitalization with an equivalent intermediate-term oncologic outcome compared with that of the open approach. Our results were in agreement with previous studies, in which perioperative and postoperative morbidities were better in HALNU than ONU.

Conclusion

We also acknowledge certain inherent limitations in the studies included in our meta-analysis, which cannot be ignored when interpreting our data. First, most of the studies included in our analysis were retrospective, which is a reflection of the rarity of the disease. Second, the clinical and pathologic characteristics of the patients were different in the included trials. Similar to the other laparoscopic procedures, the LNU might be selectively performed in risk-favorable patients at an earlier tumor stage and therefore, the results of our analysis favoring LNU could be attributed mainly to a bias in the data from the LNU study arms. Third, the urologists widely accept that the distinguished differences that exist in the biological behavior and patients' prognosis between the locoregional recurrence and the recurrence in the remnant urothelium. Finally, it is well known that the indications for LNU were much stricter than those for ONU because of the more stringent requirements for comorbidities such as body mass index, cardiopulmonary disease, and previous abdominal surgery. Despite the fact that no data on the comorbidity status have been reported in this analysis, it could be regarded as a confounder in patient selection.

Footnotes

Acknowledgments

We thank Golnaz Shemshaki for assisting in the preparation of this article. Funding: Urology and Nephrology Research Center, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Authors' Contributions

H.S. and B.J. designed the research, interpreted the data, and revised the article. A.N., S.T., M.S., and N.S. performed the data extraction, carried out the meta-analysis, and drafted the article. All the authors approved the submitted and final version.

Ethics Approval and Consent to Participate

All analyses were based on previously published studies; thus, no ethical approval and patient consent are required.

Availability of Data and Materials

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Disclosure Statement

No competing financial interests exist.

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