- Email: [email protected]
Simple tumor enucleation may not decrease oncologic outcomes for T1 renal cell carcinoma: A systematic review and meta-analysis
Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Original article
Simple tumor enucleation may not decrease oncologic outcomes for T1 renal cell carcinoma: A systematic review and meta-analysis De-Hong Cao, M.D.1, Liang-Ren Liu, M.D.1, Yu Fang, M.D., Ping Tang, M.D., Tao Li, M.D., YunJin Bai, M.D., Jia Wang, M.D.⁎, Qiang Wei, M.D.⁎ Department of Urology, Institute of Urology, West China Hospital, SiChuan University, Chengdu, China Received 19 February 2017; received in revised form 27 June 2017; accepted 10 July 2017
Abstract Objective: To evaluate the clinical efficacy and safety of simple tumor enucleation (TE) for clinical T1 renal cell carcinoma. Materials and methods: A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases was performed to identify all trials that compared TE and traditional partial nephrectomy (PN) for patients with clinical T1 renal cell carcinoma. Results: A total of 7 studies involving 3,218 patients were identified and included in this meta-analysis. Compared with the PN group, the TE group had significantly shorter estimated operation times (mean difference [MD] ¼ −21.93; 95% CI: −31.07 to −12.78; P o 0.001), shorter warm ischemia times (MD ¼ −1.96; 95% CI: −3.80 to −0.13; P ¼ 0.04), less blood loss (MD ¼ −36.63; 95% CI: −57.49 to −15.77; P ¼ 0.0006), and lower surgical complication rates (odds ratio [OR] ¼ 0.66; 95% CI: 0.47–0.92; P ¼ 0.02). Furthermore, there was no significant difference between the 2 groups in hospital stay duration (MD ¼ −0.46; 95% CI: −0.93 to 0.02; P ¼ 0.06), changes in estimated glomerular filtration rate (MD ¼ 3.35; 95% CI: −2.78 to 9.48; P ¼ 0.28), positive surgical margin rates (OR ¼ 0.34; 95% CI: 0.10–1.14; P ¼ 0.08), and local recurrence rates (OR ¼ 0.71; 95% CI: 0.24–2.06; P ¼ 0.52). Conclusion: Compared to traditional PN, TE is an effective and safe treatment for T1 renal tumors, and TE appears to have acceptable early oncology outcomes. Owing to the limited number of clinical trials and the predominantly retrospective data on this subject, there is a need for properly designed studies to confirm our findings. r 2017 Elsevier Inc. All rights reserved.
Keywords: Renal cell carcinoma; Tumor enucleation; Partial nephrectomy; Meta-analysis
1. Introduction Renal cell carcinoma (RCC) is the third most common cancer of the genitourinary system and represents approximately 3% to 5% of all adult malignancies [1,2]. The European Association of Urology and American Urological Association guidelines indicate that surgical excision is the gold standard for the management of clinical T1 tumors, with traditional partial nephrectomy (PN) being the preferred method whenever technically possible [3,4]. The rationale behind these guidelines is related to the fact that PN provides functional and oncologic results equivalent to 1
Equal study contribution and should share the cofirst author. Corresponding authors. Tel./fax: þ86-288-542-2451. E-mail addresses: [email protected] (J. Wang), [email protected] (Q. Wei). ⁎
http://dx.doi.org/10.1016/j.urolonc.2017.07.007 1078-1439/r 2017 Elsevier Inc. All rights reserved.
those of radical nephrectomy in these patients. Furthermore, for clinical T1 renal tumors, radical nephrectomy offers no increase in survival benefit but has an additional risk of renal impairment, compared with PN. The most recent studies have consistently confirmed these results [5–8]. PN has been widely adopted as the current standard treatment for T1 renal masses [3]. However, in the past few years, an increasing number of surgeons started to perform simple tumor enucleation (TE) as another procedure of nephron-sparing surgery (NSS), aiming to maximally preserve healthy parenchyma tissue and reduce the incidence of complications [9,10]. The TE method was defined as blunt dissection of the tumor following the natural cleavage plane between the normal renal tissue and the tumor pseudocapsule without a visible margin [9]. On the contrary, PN involves complete tumor excision with an additional visible margin of healthy renal parenchyma.
2
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Currently, some researchers believe that TE is a feasible, effective, and safe surgical technique for T1 renal tumors [9–11]. However, other researchers found that TE results in a positive surgical margin more frequently than does PN [12]. In addition, TE as a minimally invasive technique for the treatment of RCC is still debated [9–13]. Consequently, we performed a systematic review and meta-analysis of the available literature to evaluate the efficacy and safety of TE vs. PN for patients with RCC. 2. Materials and methods 2.1. Search strategy We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases for studies published from January 1990 to December 2016. An electronic search was performed to identify all relevant studies by using the following search terms: “simple enucleation,” “tumor enucleation,” “partial nephrectomy,” “sharp excision,” “renal cell carcinoma,” “renal cancer,” “kidney cancer,” and “renal tumor.” Furthermore, relevant literature references and conference proceedings of the EAU and AUA from 2000 to 2016 were searched manually. The process of retrieving and screening the literature was performed independently by 2 authors (D.C. and L.L.), and any difference was resolved through a discussion. 2.2. Selection criteria Studies comparing TE with PN for the treatment of RCC were included in this meta-analysis. The inclusion criteria were as follows: (1) the study patients were diagnosed as having T1 RCC; (2) the surgical approach was laparoscopic, robotic, and open. Studies were excluded according to the following criteria: (1) the article type was a case report, review, letter, or comments; (2) there was a lack of a comparative control group; (3) there were a lack of quantitative data; and (4) the study participants were not patients with RCC. If multiple studies were published by the same group with overlapping patient populations, we chose the largest sample study. 2.3. Study quality assessment The quality of the included randomized controlled trials was assessed according to the Cochrane Collaboration Reviewers' Handbook [14]. The quality standards consisted of the following domains: generation of randomization sequences, allocation concealment, blinding, incomplete outcome data, freedom from selective reporting, and freedom from other biases. Nonrandomized studies were assessed using a modification of the Newcastle-Ottawa Scale (NOS) [15]. Studies with review scores ranging from 0 to 5 were defined as low quality, whereas those with
Newcastle-Ottawa Scale scores with 6 or more stars were defined as high quality. All included studies were independently assessed by 2 reviewers. Discrepancies were resolved through consensus. 2.4. Data extraction Two authors independently extracted the data from all included studies, following a predesigned data extraction form. The following basic study features were extracted: study design, first author, year of publication, sample size, age, body mass index, tumor size, surgical approach, and follow-up period. In addition, the primary outcome measures included the following independent variables: perioperative and postoperative data (operation time, warm ischemia time [WIT], defined as the time of renal artery clamping, blood loss, surgical complication rate, and hospital stay duration), functional outcome (change in estimated glomerular filtration rate [eGFR]), and oncologic outcomes (rates of positive surgical margin and local recurrence). 2.5. Statistical analysis Statistical analysis was implemented with Review Manager (RevMan) software version 5.2.0 (Cochrane Collaboration, Oxford, UK). The odds ratio (OR) was used to evaluate dichotomous data, and the mean difference (MD) was used to evaluate continuous data. The 95% CIs were also computed. The I2 test was used to test for heterogeneity (P o 0.1 or I2 4 50%). If the pooled result had an acceptable level of heterogeneity, a fixed-effects model was used; otherwise, a random-effects model was used. If continuous variables appeared as medians and ranges in the primary literature, we calculated the mean and standard deviation for this meta-analysis [16]. Sensitivity analysis was implemented for the included low-quality studies. 3. Results 3.1. Description of studies Initially, 326 articles were identified and manually retrieved from the databases. A total of 174 publications were removed because of duplication. After reading the titles and abstracts, 113 unrelated articles were excluded. Furthermore, 32 articles were excluded after reading the full text. Finally, a total of 7 studies involving 3,218 patients were identified for quantitative analysis [12,17–22]. It is worth noting that to avoid overlapping dates between studies from the same group, we chose the article with a larger sample size [22] and excluded the article with a smaller sample size from Minervini et al. [23]. A total of 1 randomized controlled trial [19] and 6 retrospective studies were included [12,17,18,20–22]. Fig. 1 shows the process
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
3
CI: 0.10–1.14; P ¼ 0.08) and local recurrence (OR ¼ 0.71; 95% CI: 0.24–2.06; P ¼ 0.52).
4. Discussion
Fig. 1. Flow diagram of evidence acquisition.
of screening. The characteristics and quality assessments of the included studies are summarized in the Table. 3.2. Perioperative and postoperative variables Figs. 2 and 3 show the pooled results of preoperative and postoperative variables, including operation times, WITs, blood loss, surgical complication rates, and hospital stay durations. As shown in Fig. 2, the TE group had a significantly shorter estimated operation time (MD ¼ −21.93; 95% CI: −31.07 to −12.78; P o 0.001), shorter WIT (MD ¼ −1.96; 95% CI: −3.80 to −0.13; P ¼ 0.04), less blood loss (MD ¼ −36.63; 95% CI: −57.49 to −15.77; P ¼ 0.0006), and lower surgical complication rate (OR ¼ 0.66; 95% CI: 0.47–0.92; P ¼ 0.02) than the PN group. In addition, as Fig. 3 shows, there was no significant difference between the 2 groups in hospital stay duration (MD ¼ −0.46; 95% CI: −0.93 to 0.02; P ¼ 0.06). 3.3. Functional variables Renal functional outcomes were assessed by using the change in eGFR in a subset of 1,097 patients. Of these patients, 423 underwent TE and 674 underwent PN. There was no significant difference between the 2 groups concerning changes in eGFR (MD ¼ 3.35; 95% CI: −2.78 to 9.48; P ¼ 0.28; Fig. 3). 3.4. Oncologic outcomes As Fig. 3 shows, the positive surgical margin and local recurrence rates in the included studies were 20 (1.89%) and 4 (0.57%) in the TE group and 70 (4.72%) and 21 (1.44%) in the PN group, respectively. However, there was no significant difference between the 2 groups in the incidence of a positive surgical margin (OR ¼ 0.34; 95%
Researchers have suggested that a margin of normal tissue should be excised with a tumor to avoid the risk of local recurrence in RCC [24]. As TE is performed by means of blunt dissection with no visible rim of normal tissue, the evaluation of the surgical margin and its usefulness as a prognostic factor have a broad consensus. However, various studies have used perioperative and postoperative variables, renal functional variables, and other oncologic outcomes in comparing TE with PN in the treatment of RCC. Although published studies showed some advantages of TE over PN, data on the safety and long-term oncologic outcomes with TE remain limited [25]. We included 7 studies involving 8 variables to assess these problems. To our knowledge, this is the first systematic review and meta-analysis to evaluate these data between the TE and PN techniques. Optimal outcomes of NSS included oncologic efficacy, preservation of renal function, and surgical safety [26]. First, the obvious concerns with this technique were the positive margin rates and oncologic outcomes, because some researchers have suggested that local recurrence may occur secondary to incomplete removal. In the included studies, the total rates of positive margins with TE and PN were 1.9% (20 of 1,058) and 4.7% (70 of 1,482), respectively. However, the pooled results of the present meta-analysis showed that there was no statistically significant difference between the 2 groups. Furthermore, we performed sensitivity analyses to test the stability of the results. We found that TE achieved lower positive margin rates compared with PN when the study of Wang et al. [12] was removed. In fact, more studies have demonstrated that there is no association between margin size and recurrence of RCC. Mukkamala et al. [27] reported the long-term oncologic outcomes and survival estimates of TE for RCC. Their results from multivariate analysis showed that only tumor stage was associated with recurrence. Positive margins or the TE or PN method did not influence recurrence or survival. Furthermore, the oncologic safety of the TE technique remains to be evaluated with a long-term follow-up. Lapini et al. [24] retrospectively evaluated the incidence of local recurrence in 107 patients who underwent TE for the treatment of small RCC. Their study suggested that the local recurrence rate was 1.9%. In addition, it was not associated with an increased risk of local recurrence compared with PN. Their study also indicated that the incidence of local recurrence because of tumor multifocality was not related to the resection margins. This present metaanalysis demonstrated that TE has a potential advantage in terms of the positive surgical margin rate and local recurrence rate compared with PN, although there were no
4
Study
Surgical method
Tumor enucleation/partial nephrectomy
Quality assessment
Outcome measures
6
WIT, PSM, and GFR
Male/ female
Age
Body mass index
Tumor size
Follow-up (mo)
Patients (n)
34:23/ 31:22
60.1 (49.2–70.4)/57.6 (48.8–63.2)
31.1 (27.9–36.3)/31.1 (27.8–36.4)
3.0 (2.1–3.6)/2.5 (2.2–3.5)
7.2 (4.2–16.3)/7.2 (4.2–16.3)
57/53
Lu et al. [18] L
170:110/ 65:40
54.9 ± 13.6/53.0 ± 14.5
ND
3.8 ± 1.4/3.8 ± 1.6 20.3/17.6
280/105 5
OT, WIT, blood loss, PSM, complications, hospital stay, and GFR
Wang et al. [12]
ND
35:24/ 29:29
57.7 (31–80)/62.1 (24–83)
ND
2.99 (1.0–6.0)/3.01 22 (11–40)/19 (1.0–6.5) (8–42)
59/58
5
OT, PSM, hospital stay, complications, and local recurrence
Huang et al. [19]
L
34:10/ 28:17
51 (27–75)/52 (25–71) 24.8 (19.4–35.5)/24.4 (20.0–32.6)
2.65 (1.2–4.0)/3.0 (1.5–4.0)
44/45
Low risk
OT, WIT, blood loss, hospital stay, GFR, local recurrence, and complications
Mukkama-la et al. [20]
L and RAL
ND
57 ± 14/58 ± 13
30 ± 7.6/30 ± 6.5
2.9 ± 1.6/2.9 ± 1.4 34.8/34.8
86/516
6
OT, blood loss, WIT, PSM, GFR, complications, and local recurrence
Longo et al. [21]
L and open
124:74/ 141:57
62.8 ± 11.5/62.4 ± 12.2
26.5 ± 3.9/26.4 ± 3.9 3.0±1.2/3.0±1.4
Minervini et al. [22]
ND
361:176/ 61.8 ± 13/60.1 ± 12.9 ND 695:287
Blackwell et al. [17]
RAL
18/18
ND
3.2 ± 1.4/3.5 ± 1.7 54.4 ± 36/51 ± 37.8
198/198 6
WIT, OT, blood loss, PSM, and complications
537/982 6
PSM and local recurrence
Continuous variables were reported as mean ± standard deviation (SD) and range as median and interquartile range. WIT ¼ warm ischemia time; PSM ¼ positive surgical margins; GFR ¼ change in estimated glomerular filtration rate; OT ¼ operative time; ND ¼ not determined; RAL ¼ robotic-assisted laparoscopy; L ¼ laparoscopic.
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Table Characteristic of the included studies
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
5
Fig. 2. Forest plot of (A) operation time, (B) warm ischemia time, (C) less blood loss, and (D) surgical complication rate between TE and PN group.
statistically significant differences between the 2 groups. These data demonstrate that TE is oncologically safe for RCC. Certainly, further studies with a larger series, longer follow-up, and higher levels of evidence to compare the roles of the 2 methods are needed to investigate the oncological results of NSS. Second, in our included studies, although Longo et al. [21] showed similar mean WITs (18 and 17.8 minute in the TE and PN groups, respectively), other studies and our results showed that the TE group had a shorter WIT than the PN group, and there was a statistically significant difference between the 2 groups. In reality, the TE method reduced entry into the renal sinus, and therefore required tumor bed suturing less frequently. There was also a decreased frequency of severe bleeding. These factors helped achieve a shorter WIT than that with the PN method. In addition, these factors also helped reduce the operation times, blood loss, and complications with the TE technique. Indeed, our meta-analysis results confirmed the excellent results of TE including shorter operation times and less blood loss.
Third, the current meta-analysis showed that the TE had better safety than the PN. The observed complication rates were 1.9% (20 of 1,058) in the TE group and 4.7% (70 of 1,482) in the PN group. Other researchers have already published similar results [18–21]. Bleeding and urine leak complications may be hypothetically minimized because entry into collection system and surrounding parenchyma is minimized with TE, which might contribute to the lower complications rates. In addition, the TE technique preserved more normal renal parenchyma and avoided damaging the residual renal parenchyma by reducing or eliminating WIT in patients undergoing NSS, which would theoretically benefit renal function. In fact, our meta-analysis results showed that there was a similar decrease in the eGFR of the affected kidney between the 2 methods, and the difference did not reach statistical significance. Our results may be limited by the small number of included studies; further assessments are warranted in the future if more studies are published on this topic. Nevertheless, our results suggested that the functional results of TE are not inferior to those of PN.
6
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Fig. 3. Forest plot of (A) hospital stay, (B) change in eGFR, (C) positive surgical margin rate, and (D) local recurrence rate between TE and PN group.
The present study has some limitations. First, the number of included clinical studies was limited, and there was no analysis of subgroups stratified according to specific surgical options such as laparoscopic or robotic-assisted laparoscopic surgery. Second, based on the available literature to date, the results are limited by a predominantly retrospective data; thus, case selection may have caused a bias. Third, some studies failed to provide means and standard deviations for continuous variables. For example, for changes in eGFR, we had to calculate these data through statistical methods. Fourth, the follow-up periods of the included studies were not identical; thus, it may not be reasonable to group studies with different follow-up durations when making comparisons.
5. Conclusions Compared with PN, TE is an effective and safe treatment for T1 renal tumors, with the caveat that case selection is
essential. TE is an option as it has acceptable early oncology outcomes than PN. Owing to the limited number of clinical trials and the predominantly retrospective data on this subject, there is a need for properly designed studies to confirm our findings. Acknowledgment This research was funded by the Natural Science Foundation of China, China (Grant nos. 81370855 and 81200551). References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. [2] Lipworth L, Tarone RE, McLaughlin JK. The epidemiology of renal cell carcinoma. J Urol 2006;176:2353–8. [3] Liss MA, Wang S, Palazzi K, et al. Evaluation of national trends in the utilization of partial nephrectomy in relation to the publication of
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
[4] [5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
the American Urologic Association guidelines for the management of clinical T1 renal masses. BMC Urol 2014;14:101. Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015;67:913–24. Lai TC, Ma WK, Yiu MK. Partial nephrectomy for T1 renal cancer can achieve an equivalent oncological outcome to radical nephrectomy with better renal preservation: the way to go. Hong Kong Med J 2016;22:39–45. Danzig MR, Ghandour RA, Chang P, et al. Active surveillance is superior to radical nephrectomy and equivalent to partial nephrectomy for preserving renal function in patients with small renal masses: results from the DISSRM registry. J Urol 2015;194:903–9. Meskawi M, Becker A, Bianchi M, et al. Partial and radical nephrectomy provide comparable long-term cancer control for T1b renal cell carcinoma. Int J Urol 2014;21:122–8. Hadjipavlou M, Khan F, Fowler S, et al. Partial vs radical nephrectomy for T1 renal tumours: an analysis from the British Association of Urological Surgeons Nephrectomy Audit. BJU Int 2016;117:62–71. García AG, León TG. Simple enucleation for renal tumors: indications, techniques, and results. Curr Urol Rep 2016;17:7. Pansadoro A, Cochetti G, D'amico F, et al. Retroperitoneal laparoscopic renal tumour enucleation with local hypotension on demand. World J Urol 2015;33:427–32. Minervini A, Rosaria Raspollini M, Tuccio A, et al. Pathological characteristics and prognostic effect of peritumoral capsule penetration in renal cell carcinoma after tumor enucleation. Urol Oncol 2014;32:50.e15-e22. Wang L, Hughes I, Snarskis C, et al. Tumor enucleation specimens of small renal tumors more frequently have a positive surgical margin than partial nephrectomy specimens, but this is not associated with local tumor recurrence. Virchows Arch 2017;470:55–61. Ficarra V, Galfano A, Cavalleri S. Is simple enucleation a minimal partial nephrectomy responding to the EAU guidelines' recommendations? Eur Urol 2009;55:1315–8. Higgins JPT, Green SE. editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available at: http://www.cochrane-hand book.org; 2011. Wells GA, Shea B, O′Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses. Available at: http://www.ohri.ca/programs/clinical_epidemi ology/oxford.asp [accessed December 20, 2016].
7
[16] Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. [17] Blackwell RH, Li B, Kozel Z, et al. Functional Implications of renal tumor enucleation relative to standard partial nephrectomy. Urology 2017;99:162–8. [18] Lu Q, Zhao X, Ji C, et al. Modified laparoscopic simple enucleation with single-layer suture technique versus standard laparoscopic partial nephrectomy for treating localized renal cell carcinoma. Int Urol Nephrol 2017;49:239–45. [19] Huang J, Zhang J, Wang Y, et al. Comparing zero ischemia laparoscopic radio frequency ablation assisted tumor enucleation and laparoscopic partial nephrectomy for clinical T1a renal tumor: A Randomized Clinical Trial. J Urol 2016;195:1677–83. [20] Mukkamala A, Allam CL, Ellison JS, et al. Tumor enucleation vs. sharp excision in minimally invasive partial nephrectomy: technical benefit without impact on functional or oncologic outcomes. Urology 2014;83:1294–9. [21] Longo N, Minervini A, Antonelli A, et al. Simple enucleation versus standard partial nephrectomy for clinical T1 renal masses: perioperative outcomes based on a matched-pair comparison of 396 patients (RECORd project). Eur J Surg Oncol 2014;40:762–8. [22] Minervini A, Ficarra V, Rocco F, et al. Simple enucleation is equivalent to traditional partial nephrectomy for renal cell carcinoma: results of a nonrandomized, retrospective, comparative study. J Urol 2011;185:1604–10. [23] Minervini A, Serni S, Tuccio A, et al. Simple enucleation versus radical nephrectomy in the treatment of pT1a and pT1b renal cell carcinoma. Ann Surg Oncol 2012;19:694–700. [24] Lapini A, Serni S, Minervini A, et al. Progression and long-term survival after simple enucleation for the elective treatment of renal cell carcinoma: experience in 107 patients. J Urol 2005;174:57–60. [25] Touijer K, Jacqmin D, Kavoussi LR, et al. The expanding role of partial nephrectomy: a critical analysis of indications, results, and complications. Eur Urol 2010;57:214–22. [26] Buffi N, Lista G, Larcher A, et al. Margin, ischemia, and complications (MIC) score in partial nephrectomy: a new system for evaluating achievement of optimal outcomes in nephron-sparing surgery. Eur Urol 2012;62:617–8. [27] Mukkamala A, He C, Weizer AZ, et al. Long-term oncologic outcomes of minimally invasive partial nephrectomy for renal-cell carcinoma. J Endourol 2014;28:649–54.
Original article
Simple tumor enucleation may not decrease oncologic outcomes for T1 renal cell carcinoma: A systematic review and meta-analysis De-Hong Cao, M.D.1, Liang-Ren Liu, M.D.1, Yu Fang, M.D., Ping Tang, M.D., Tao Li, M.D., YunJin Bai, M.D., Jia Wang, M.D.⁎, Qiang Wei, M.D.⁎ Department of Urology, Institute of Urology, West China Hospital, SiChuan University, Chengdu, China Received 19 February 2017; received in revised form 27 June 2017; accepted 10 July 2017
Abstract Objective: To evaluate the clinical efficacy and safety of simple tumor enucleation (TE) for clinical T1 renal cell carcinoma. Materials and methods: A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases was performed to identify all trials that compared TE and traditional partial nephrectomy (PN) for patients with clinical T1 renal cell carcinoma. Results: A total of 7 studies involving 3,218 patients were identified and included in this meta-analysis. Compared with the PN group, the TE group had significantly shorter estimated operation times (mean difference [MD] ¼ −21.93; 95% CI: −31.07 to −12.78; P o 0.001), shorter warm ischemia times (MD ¼ −1.96; 95% CI: −3.80 to −0.13; P ¼ 0.04), less blood loss (MD ¼ −36.63; 95% CI: −57.49 to −15.77; P ¼ 0.0006), and lower surgical complication rates (odds ratio [OR] ¼ 0.66; 95% CI: 0.47–0.92; P ¼ 0.02). Furthermore, there was no significant difference between the 2 groups in hospital stay duration (MD ¼ −0.46; 95% CI: −0.93 to 0.02; P ¼ 0.06), changes in estimated glomerular filtration rate (MD ¼ 3.35; 95% CI: −2.78 to 9.48; P ¼ 0.28), positive surgical margin rates (OR ¼ 0.34; 95% CI: 0.10–1.14; P ¼ 0.08), and local recurrence rates (OR ¼ 0.71; 95% CI: 0.24–2.06; P ¼ 0.52). Conclusion: Compared to traditional PN, TE is an effective and safe treatment for T1 renal tumors, and TE appears to have acceptable early oncology outcomes. Owing to the limited number of clinical trials and the predominantly retrospective data on this subject, there is a need for properly designed studies to confirm our findings. r 2017 Elsevier Inc. All rights reserved.
Keywords: Renal cell carcinoma; Tumor enucleation; Partial nephrectomy; Meta-analysis
1. Introduction Renal cell carcinoma (RCC) is the third most common cancer of the genitourinary system and represents approximately 3% to 5% of all adult malignancies [1,2]. The European Association of Urology and American Urological Association guidelines indicate that surgical excision is the gold standard for the management of clinical T1 tumors, with traditional partial nephrectomy (PN) being the preferred method whenever technically possible [3,4]. The rationale behind these guidelines is related to the fact that PN provides functional and oncologic results equivalent to 1
Equal study contribution and should share the cofirst author. Corresponding authors. Tel./fax: þ86-288-542-2451. E-mail addresses: [email protected] (J. Wang), [email protected] (Q. Wei). ⁎
http://dx.doi.org/10.1016/j.urolonc.2017.07.007 1078-1439/r 2017 Elsevier Inc. All rights reserved.
those of radical nephrectomy in these patients. Furthermore, for clinical T1 renal tumors, radical nephrectomy offers no increase in survival benefit but has an additional risk of renal impairment, compared with PN. The most recent studies have consistently confirmed these results [5–8]. PN has been widely adopted as the current standard treatment for T1 renal masses [3]. However, in the past few years, an increasing number of surgeons started to perform simple tumor enucleation (TE) as another procedure of nephron-sparing surgery (NSS), aiming to maximally preserve healthy parenchyma tissue and reduce the incidence of complications [9,10]. The TE method was defined as blunt dissection of the tumor following the natural cleavage plane between the normal renal tissue and the tumor pseudocapsule without a visible margin [9]. On the contrary, PN involves complete tumor excision with an additional visible margin of healthy renal parenchyma.
2
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Currently, some researchers believe that TE is a feasible, effective, and safe surgical technique for T1 renal tumors [9–11]. However, other researchers found that TE results in a positive surgical margin more frequently than does PN [12]. In addition, TE as a minimally invasive technique for the treatment of RCC is still debated [9–13]. Consequently, we performed a systematic review and meta-analysis of the available literature to evaluate the efficacy and safety of TE vs. PN for patients with RCC. 2. Materials and methods 2.1. Search strategy We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases for studies published from January 1990 to December 2016. An electronic search was performed to identify all relevant studies by using the following search terms: “simple enucleation,” “tumor enucleation,” “partial nephrectomy,” “sharp excision,” “renal cell carcinoma,” “renal cancer,” “kidney cancer,” and “renal tumor.” Furthermore, relevant literature references and conference proceedings of the EAU and AUA from 2000 to 2016 were searched manually. The process of retrieving and screening the literature was performed independently by 2 authors (D.C. and L.L.), and any difference was resolved through a discussion. 2.2. Selection criteria Studies comparing TE with PN for the treatment of RCC were included in this meta-analysis. The inclusion criteria were as follows: (1) the study patients were diagnosed as having T1 RCC; (2) the surgical approach was laparoscopic, robotic, and open. Studies were excluded according to the following criteria: (1) the article type was a case report, review, letter, or comments; (2) there was a lack of a comparative control group; (3) there were a lack of quantitative data; and (4) the study participants were not patients with RCC. If multiple studies were published by the same group with overlapping patient populations, we chose the largest sample study. 2.3. Study quality assessment The quality of the included randomized controlled trials was assessed according to the Cochrane Collaboration Reviewers' Handbook [14]. The quality standards consisted of the following domains: generation of randomization sequences, allocation concealment, blinding, incomplete outcome data, freedom from selective reporting, and freedom from other biases. Nonrandomized studies were assessed using a modification of the Newcastle-Ottawa Scale (NOS) [15]. Studies with review scores ranging from 0 to 5 were defined as low quality, whereas those with
Newcastle-Ottawa Scale scores with 6 or more stars were defined as high quality. All included studies were independently assessed by 2 reviewers. Discrepancies were resolved through consensus. 2.4. Data extraction Two authors independently extracted the data from all included studies, following a predesigned data extraction form. The following basic study features were extracted: study design, first author, year of publication, sample size, age, body mass index, tumor size, surgical approach, and follow-up period. In addition, the primary outcome measures included the following independent variables: perioperative and postoperative data (operation time, warm ischemia time [WIT], defined as the time of renal artery clamping, blood loss, surgical complication rate, and hospital stay duration), functional outcome (change in estimated glomerular filtration rate [eGFR]), and oncologic outcomes (rates of positive surgical margin and local recurrence). 2.5. Statistical analysis Statistical analysis was implemented with Review Manager (RevMan) software version 5.2.0 (Cochrane Collaboration, Oxford, UK). The odds ratio (OR) was used to evaluate dichotomous data, and the mean difference (MD) was used to evaluate continuous data. The 95% CIs were also computed. The I2 test was used to test for heterogeneity (P o 0.1 or I2 4 50%). If the pooled result had an acceptable level of heterogeneity, a fixed-effects model was used; otherwise, a random-effects model was used. If continuous variables appeared as medians and ranges in the primary literature, we calculated the mean and standard deviation for this meta-analysis [16]. Sensitivity analysis was implemented for the included low-quality studies. 3. Results 3.1. Description of studies Initially, 326 articles were identified and manually retrieved from the databases. A total of 174 publications were removed because of duplication. After reading the titles and abstracts, 113 unrelated articles were excluded. Furthermore, 32 articles were excluded after reading the full text. Finally, a total of 7 studies involving 3,218 patients were identified for quantitative analysis [12,17–22]. It is worth noting that to avoid overlapping dates between studies from the same group, we chose the article with a larger sample size [22] and excluded the article with a smaller sample size from Minervini et al. [23]. A total of 1 randomized controlled trial [19] and 6 retrospective studies were included [12,17,18,20–22]. Fig. 1 shows the process
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
3
CI: 0.10–1.14; P ¼ 0.08) and local recurrence (OR ¼ 0.71; 95% CI: 0.24–2.06; P ¼ 0.52).
4. Discussion
Fig. 1. Flow diagram of evidence acquisition.
of screening. The characteristics and quality assessments of the included studies are summarized in the Table. 3.2. Perioperative and postoperative variables Figs. 2 and 3 show the pooled results of preoperative and postoperative variables, including operation times, WITs, blood loss, surgical complication rates, and hospital stay durations. As shown in Fig. 2, the TE group had a significantly shorter estimated operation time (MD ¼ −21.93; 95% CI: −31.07 to −12.78; P o 0.001), shorter WIT (MD ¼ −1.96; 95% CI: −3.80 to −0.13; P ¼ 0.04), less blood loss (MD ¼ −36.63; 95% CI: −57.49 to −15.77; P ¼ 0.0006), and lower surgical complication rate (OR ¼ 0.66; 95% CI: 0.47–0.92; P ¼ 0.02) than the PN group. In addition, as Fig. 3 shows, there was no significant difference between the 2 groups in hospital stay duration (MD ¼ −0.46; 95% CI: −0.93 to 0.02; P ¼ 0.06). 3.3. Functional variables Renal functional outcomes were assessed by using the change in eGFR in a subset of 1,097 patients. Of these patients, 423 underwent TE and 674 underwent PN. There was no significant difference between the 2 groups concerning changes in eGFR (MD ¼ 3.35; 95% CI: −2.78 to 9.48; P ¼ 0.28; Fig. 3). 3.4. Oncologic outcomes As Fig. 3 shows, the positive surgical margin and local recurrence rates in the included studies were 20 (1.89%) and 4 (0.57%) in the TE group and 70 (4.72%) and 21 (1.44%) in the PN group, respectively. However, there was no significant difference between the 2 groups in the incidence of a positive surgical margin (OR ¼ 0.34; 95%
Researchers have suggested that a margin of normal tissue should be excised with a tumor to avoid the risk of local recurrence in RCC [24]. As TE is performed by means of blunt dissection with no visible rim of normal tissue, the evaluation of the surgical margin and its usefulness as a prognostic factor have a broad consensus. However, various studies have used perioperative and postoperative variables, renal functional variables, and other oncologic outcomes in comparing TE with PN in the treatment of RCC. Although published studies showed some advantages of TE over PN, data on the safety and long-term oncologic outcomes with TE remain limited [25]. We included 7 studies involving 8 variables to assess these problems. To our knowledge, this is the first systematic review and meta-analysis to evaluate these data between the TE and PN techniques. Optimal outcomes of NSS included oncologic efficacy, preservation of renal function, and surgical safety [26]. First, the obvious concerns with this technique were the positive margin rates and oncologic outcomes, because some researchers have suggested that local recurrence may occur secondary to incomplete removal. In the included studies, the total rates of positive margins with TE and PN were 1.9% (20 of 1,058) and 4.7% (70 of 1,482), respectively. However, the pooled results of the present meta-analysis showed that there was no statistically significant difference between the 2 groups. Furthermore, we performed sensitivity analyses to test the stability of the results. We found that TE achieved lower positive margin rates compared with PN when the study of Wang et al. [12] was removed. In fact, more studies have demonstrated that there is no association between margin size and recurrence of RCC. Mukkamala et al. [27] reported the long-term oncologic outcomes and survival estimates of TE for RCC. Their results from multivariate analysis showed that only tumor stage was associated with recurrence. Positive margins or the TE or PN method did not influence recurrence or survival. Furthermore, the oncologic safety of the TE technique remains to be evaluated with a long-term follow-up. Lapini et al. [24] retrospectively evaluated the incidence of local recurrence in 107 patients who underwent TE for the treatment of small RCC. Their study suggested that the local recurrence rate was 1.9%. In addition, it was not associated with an increased risk of local recurrence compared with PN. Their study also indicated that the incidence of local recurrence because of tumor multifocality was not related to the resection margins. This present metaanalysis demonstrated that TE has a potential advantage in terms of the positive surgical margin rate and local recurrence rate compared with PN, although there were no
4
Study
Surgical method
Tumor enucleation/partial nephrectomy
Quality assessment
Outcome measures
6
WIT, PSM, and GFR
Male/ female
Age
Body mass index
Tumor size
Follow-up (mo)
Patients (n)
34:23/ 31:22
60.1 (49.2–70.4)/57.6 (48.8–63.2)
31.1 (27.9–36.3)/31.1 (27.8–36.4)
3.0 (2.1–3.6)/2.5 (2.2–3.5)
7.2 (4.2–16.3)/7.2 (4.2–16.3)
57/53
Lu et al. [18] L
170:110/ 65:40
54.9 ± 13.6/53.0 ± 14.5
ND
3.8 ± 1.4/3.8 ± 1.6 20.3/17.6
280/105 5
OT, WIT, blood loss, PSM, complications, hospital stay, and GFR
Wang et al. [12]
ND
35:24/ 29:29
57.7 (31–80)/62.1 (24–83)
ND
2.99 (1.0–6.0)/3.01 22 (11–40)/19 (1.0–6.5) (8–42)
59/58
5
OT, PSM, hospital stay, complications, and local recurrence
Huang et al. [19]
L
34:10/ 28:17
51 (27–75)/52 (25–71) 24.8 (19.4–35.5)/24.4 (20.0–32.6)
2.65 (1.2–4.0)/3.0 (1.5–4.0)
44/45
Low risk
OT, WIT, blood loss, hospital stay, GFR, local recurrence, and complications
Mukkama-la et al. [20]
L and RAL
ND
57 ± 14/58 ± 13
30 ± 7.6/30 ± 6.5
2.9 ± 1.6/2.9 ± 1.4 34.8/34.8
86/516
6
OT, blood loss, WIT, PSM, GFR, complications, and local recurrence
Longo et al. [21]
L and open
124:74/ 141:57
62.8 ± 11.5/62.4 ± 12.2
26.5 ± 3.9/26.4 ± 3.9 3.0±1.2/3.0±1.4
Minervini et al. [22]
ND
361:176/ 61.8 ± 13/60.1 ± 12.9 ND 695:287
Blackwell et al. [17]
RAL
18/18
ND
3.2 ± 1.4/3.5 ± 1.7 54.4 ± 36/51 ± 37.8
198/198 6
WIT, OT, blood loss, PSM, and complications
537/982 6
PSM and local recurrence
Continuous variables were reported as mean ± standard deviation (SD) and range as median and interquartile range. WIT ¼ warm ischemia time; PSM ¼ positive surgical margins; GFR ¼ change in estimated glomerular filtration rate; OT ¼ operative time; ND ¼ not determined; RAL ¼ robotic-assisted laparoscopy; L ¼ laparoscopic.
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Table Characteristic of the included studies
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
5
Fig. 2. Forest plot of (A) operation time, (B) warm ischemia time, (C) less blood loss, and (D) surgical complication rate between TE and PN group.
statistically significant differences between the 2 groups. These data demonstrate that TE is oncologically safe for RCC. Certainly, further studies with a larger series, longer follow-up, and higher levels of evidence to compare the roles of the 2 methods are needed to investigate the oncological results of NSS. Second, in our included studies, although Longo et al. [21] showed similar mean WITs (18 and 17.8 minute in the TE and PN groups, respectively), other studies and our results showed that the TE group had a shorter WIT than the PN group, and there was a statistically significant difference between the 2 groups. In reality, the TE method reduced entry into the renal sinus, and therefore required tumor bed suturing less frequently. There was also a decreased frequency of severe bleeding. These factors helped achieve a shorter WIT than that with the PN method. In addition, these factors also helped reduce the operation times, blood loss, and complications with the TE technique. Indeed, our meta-analysis results confirmed the excellent results of TE including shorter operation times and less blood loss.
Third, the current meta-analysis showed that the TE had better safety than the PN. The observed complication rates were 1.9% (20 of 1,058) in the TE group and 4.7% (70 of 1,482) in the PN group. Other researchers have already published similar results [18–21]. Bleeding and urine leak complications may be hypothetically minimized because entry into collection system and surrounding parenchyma is minimized with TE, which might contribute to the lower complications rates. In addition, the TE technique preserved more normal renal parenchyma and avoided damaging the residual renal parenchyma by reducing or eliminating WIT in patients undergoing NSS, which would theoretically benefit renal function. In fact, our meta-analysis results showed that there was a similar decrease in the eGFR of the affected kidney between the 2 methods, and the difference did not reach statistical significance. Our results may be limited by the small number of included studies; further assessments are warranted in the future if more studies are published on this topic. Nevertheless, our results suggested that the functional results of TE are not inferior to those of PN.
6
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
Fig. 3. Forest plot of (A) hospital stay, (B) change in eGFR, (C) positive surgical margin rate, and (D) local recurrence rate between TE and PN group.
The present study has some limitations. First, the number of included clinical studies was limited, and there was no analysis of subgroups stratified according to specific surgical options such as laparoscopic or robotic-assisted laparoscopic surgery. Second, based on the available literature to date, the results are limited by a predominantly retrospective data; thus, case selection may have caused a bias. Third, some studies failed to provide means and standard deviations for continuous variables. For example, for changes in eGFR, we had to calculate these data through statistical methods. Fourth, the follow-up periods of the included studies were not identical; thus, it may not be reasonable to group studies with different follow-up durations when making comparisons.
5. Conclusions Compared with PN, TE is an effective and safe treatment for T1 renal tumors, with the caveat that case selection is
essential. TE is an option as it has acceptable early oncology outcomes than PN. Owing to the limited number of clinical trials and the predominantly retrospective data on this subject, there is a need for properly designed studies to confirm our findings. Acknowledgment This research was funded by the Natural Science Foundation of China, China (Grant nos. 81370855 and 81200551). References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. [2] Lipworth L, Tarone RE, McLaughlin JK. The epidemiology of renal cell carcinoma. J Urol 2006;176:2353–8. [3] Liss MA, Wang S, Palazzi K, et al. Evaluation of national trends in the utilization of partial nephrectomy in relation to the publication of
D.-H. Cao et al. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
[4] [5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
the American Urologic Association guidelines for the management of clinical T1 renal masses. BMC Urol 2014;14:101. Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015;67:913–24. Lai TC, Ma WK, Yiu MK. Partial nephrectomy for T1 renal cancer can achieve an equivalent oncological outcome to radical nephrectomy with better renal preservation: the way to go. Hong Kong Med J 2016;22:39–45. Danzig MR, Ghandour RA, Chang P, et al. Active surveillance is superior to radical nephrectomy and equivalent to partial nephrectomy for preserving renal function in patients with small renal masses: results from the DISSRM registry. J Urol 2015;194:903–9. Meskawi M, Becker A, Bianchi M, et al. Partial and radical nephrectomy provide comparable long-term cancer control for T1b renal cell carcinoma. Int J Urol 2014;21:122–8. Hadjipavlou M, Khan F, Fowler S, et al. Partial vs radical nephrectomy for T1 renal tumours: an analysis from the British Association of Urological Surgeons Nephrectomy Audit. BJU Int 2016;117:62–71. García AG, León TG. Simple enucleation for renal tumors: indications, techniques, and results. Curr Urol Rep 2016;17:7. Pansadoro A, Cochetti G, D'amico F, et al. Retroperitoneal laparoscopic renal tumour enucleation with local hypotension on demand. World J Urol 2015;33:427–32. Minervini A, Rosaria Raspollini M, Tuccio A, et al. Pathological characteristics and prognostic effect of peritumoral capsule penetration in renal cell carcinoma after tumor enucleation. Urol Oncol 2014;32:50.e15-e22. Wang L, Hughes I, Snarskis C, et al. Tumor enucleation specimens of small renal tumors more frequently have a positive surgical margin than partial nephrectomy specimens, but this is not associated with local tumor recurrence. Virchows Arch 2017;470:55–61. Ficarra V, Galfano A, Cavalleri S. Is simple enucleation a minimal partial nephrectomy responding to the EAU guidelines' recommendations? Eur Urol 2009;55:1315–8. Higgins JPT, Green SE. editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available at: http://www.cochrane-hand book.org; 2011. Wells GA, Shea B, O′Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses. Available at: http://www.ohri.ca/programs/clinical_epidemi ology/oxford.asp [accessed December 20, 2016].
7
[16] Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. [17] Blackwell RH, Li B, Kozel Z, et al. Functional Implications of renal tumor enucleation relative to standard partial nephrectomy. Urology 2017;99:162–8. [18] Lu Q, Zhao X, Ji C, et al. Modified laparoscopic simple enucleation with single-layer suture technique versus standard laparoscopic partial nephrectomy for treating localized renal cell carcinoma. Int Urol Nephrol 2017;49:239–45. [19] Huang J, Zhang J, Wang Y, et al. Comparing zero ischemia laparoscopic radio frequency ablation assisted tumor enucleation and laparoscopic partial nephrectomy for clinical T1a renal tumor: A Randomized Clinical Trial. J Urol 2016;195:1677–83. [20] Mukkamala A, Allam CL, Ellison JS, et al. Tumor enucleation vs. sharp excision in minimally invasive partial nephrectomy: technical benefit without impact on functional or oncologic outcomes. Urology 2014;83:1294–9. [21] Longo N, Minervini A, Antonelli A, et al. Simple enucleation versus standard partial nephrectomy for clinical T1 renal masses: perioperative outcomes based on a matched-pair comparison of 396 patients (RECORd project). Eur J Surg Oncol 2014;40:762–8. [22] Minervini A, Ficarra V, Rocco F, et al. Simple enucleation is equivalent to traditional partial nephrectomy for renal cell carcinoma: results of a nonrandomized, retrospective, comparative study. J Urol 2011;185:1604–10. [23] Minervini A, Serni S, Tuccio A, et al. Simple enucleation versus radical nephrectomy in the treatment of pT1a and pT1b renal cell carcinoma. Ann Surg Oncol 2012;19:694–700. [24] Lapini A, Serni S, Minervini A, et al. Progression and long-term survival after simple enucleation for the elective treatment of renal cell carcinoma: experience in 107 patients. J Urol 2005;174:57–60. [25] Touijer K, Jacqmin D, Kavoussi LR, et al. The expanding role of partial nephrectomy: a critical analysis of indications, results, and complications. Eur Urol 2010;57:214–22. [26] Buffi N, Lista G, Larcher A, et al. Margin, ischemia, and complications (MIC) score in partial nephrectomy: a new system for evaluating achievement of optimal outcomes in nephron-sparing surgery. Eur Urol 2012;62:617–8. [27] Mukkamala A, He C, Weizer AZ, et al. Long-term oncologic outcomes of minimally invasive partial nephrectomy for renal-cell carcinoma. J Endourol 2014;28:649–54.