Different inguinal lymphadenectomy for penile malignancy: a pairwise and Bayesian network meta-analysis

Highlights The existing guidelines recommend the use of minimally invasive inguinal lymph node dissection (LND) primarily in clinical trials involving patients with penile cancer. This meta-analysis included 1674 patients from 29 studies to assess different inguinal LND. Video-endoscopic inguinal LND (VEIL) demonstrates superiority over open inguinal LND in terms of perioperative outcomes and complications. Robot-assisted VEIL presents a promising alternative for the treatment of penile cancer. Penile cancer is an uncommon yet aggressive tumor that can develop in the skin of the glans or the inner layer of the foreskin1. The current guidelines from the European Association of Urology (EAU) and the American Society of Clinical Oncology (ASCO) strongly advocate for offering surgical staging to all patients with a high likelihood of micrometastatic disease (T1b or higher) if no palpable/suspicious lymph nodes (cN0) are detected during physical examination1. Furthermore, inguinal lymph node dissection (ILND) remains the predominant surgical approach for patients diagnosed with penile cancer2. While open inguinal lymph node dissection (OILND) is the standard surgical procedure for patients with penile cancer, its application often has a high incidence of complications3. In recent years, minimally invasive techniques have gained prominence in genitourinary oncology surgery and have exhibited superior outcomes compared to open surgery in several trials4,5. The latest guidelines from the EAU endorse minimally invasive ILND solely for stage cN1–2 patients as part of clinical trials1. To provide the most current and comprehensive evidence-based analysis, we employed pairwise and Bayesian network meta-analysis (NMA) to compare perioperative outcomes, complications, and oncologic outcomes across various ILND approaches in patients with penile cancer. We conducted this study according to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Supplementary Table S1, Supplemental Digital Content 1, https://links.lww.com/JS9/D68) and Assessing the Methodological Quality of Systematic Reviews-2 (AMSTAR-2, Supplemental Digital Content 2, https://links.lww.com/JS9/D69)6,7. The study protocol has been prospectively registered in PROSPERO. As of 15 March 2024, two reviewers independently conducted searches across multiple databases (Supplementary Table S2, Supplemental Digital Content 3, https://links.lww.com/JS9/D70). The analyses included studies meeting the following criteria: (1) randomized controlled trials (RCTs) or cohorts comparing OILND, video-endoscopic inguinal LND (VEILND), or robot-assisted video-endoscopic inguinal LND (RAVEIL) for penile cancer, and (2) studies providing sufficient data on perioperative outcomes, complications, and oncological outcomes. The Newcastle–Ottawa Scale was used to evaluate the quality of the included cohort and case-control study, and studies with seven to nine points were regarded as high quality. The quality of the included randomized trials was evaluated with the Cochrane Collaboration’s tool for assessing the risk8. The Stata 12.0 was employed for the meta-analysis to compare continuous and dichotomous data, expressed as weighted mean difference and odds ratio, respectively. We performed subgroup analyses of the race of the included study population into Asian and non-Asian populations, and whether or not the saphenous vein was preserved in the ILND. In the NMA, local inconsistency testing was conducted using a node-splitting method. The surface under the cumulative ranking curve (SUCRA) was utilized to rank each intervention and determine the optimal treatment regimen, with higher SUCRA probability indicating a greater likelihood of being the best treatment option9. NMA calculations were performed using R 4.3.2 software with the “gemtc” package version 1.0.2. Our meta-analysis included 29 articles with 1674 patients (Supplementary Fig S1, Supplemental Digital Content 4, https://links.lww.com/JS9/D71). The specific characteristics of each included study are provided in Supplementary Table S3, Supplemental Digital Content 5, https://links.lww.com/JS9/D72. In non-RCTs, the median quality score was 8 (range: 5–9), with 21 studies identified as high quality (Supplementary Table S4, Supplemental Digital Content 6, https://links.lww.com/JS9/D73). Supplementary Table S5, Supplemental Digital Content 7, https://links.lww.com/JS9/D74 and Supplementary Figs S2-S5, Supplemental Digital Content 8, https://links.lww.com/JS9/D75, Supplemental Digital Content 9, https://links.lww.com/JS9/D76, Supplemental Digital Content 10, https://links.lww.com/JS9/D77, Supplemental Digital Content 11, https://links.lww.com/JS9/D78 present the detailed results of the pairwise meta-analysis. Despite the longer surgery time for the VEIL group, it had better perioperative outcomes and fewer complications than the OILND group. Compared to OILND, RAVEIL did not exhibit significant differences in perioperative outcomes or complications. Compared to VEIL, RAVEIL was associated with a shorter hospital stay and a higher number of inguinal lymph nodes removed. Supplementary Table S5, Supplemental Digital Content 7, https://links.lww.com/JS9/D74 provides the results for heterogeneity and publication bias for each study. Sensitivity analyses revealed stable outcomes for operative time, blood loss, and drainage time (Supplementary Fig S6, Supplemental Digital Content 12, https://links.lww.com/JS9/D79). Meta-regression found that the study period (with a 5-year cut-off) may be a source of heterogeneity in operative time (P=0.043), blood loss (P=0.010), and drainage days (P=0.032). For lymph edema incidence, the main source of study heterogeneity was identified as the study by Fankhauser et al.10. Supplementary Table S6, Supplemental Digital Content 13, https://links.lww.com/JS9/D80 presents the results of subgroup analyses based on race and whether the saphenous vein was retained. Subgroup analyses revealed that drainage time, the incidence of minor complications, lymphatic leakage, and wound infection were lower for VEIL than for OILND in the Asian population, but there were no differences in the non-Asian population. The incidence of minor complications was lower for VEIL than for OILND in the group with removal of the saphenous vein, but there were no differences in the preserved saphenous vein group. Figure 1 depicts a network evidence plot of twelve outcomes. NMA yields similar results to pairwise meta-analysis (Table 1). Figure 2 shows the effects of the three inguinal LNDs on the twelve outcomes of SUCRA. Among the perioperative outcomes, OILND, VEIL, VEIL, RAVEI, and RAVEIL ranked first in terms of operation time, blood loss, drainage time, hospital stay, and number of resected inguinal lymph nodes (Fig. 2). Among the complications, VEIL ranked first in terms of the incidence of all AEs, minor complications, major complications, wound infection, and lymph edema according to the SUCRA, while RAVEIL ranked first in terms of the incidence of lymphocele. In addition, RAVEIL ranked first in terms of disease recurrence. To determine the outcomes of the formation of the closed loop, a localized cleavage method was applied to explore potential inconsistencies. No inconsistency was detected in terms of operative time or disease recurrence (Supplementary Fig S7, Supplemental Digital Content 14, https://links.lww.com/JS9/D81). However, inconsistency was found in the number of inguinal lymph nodes removed.Figure 1: Network plots comparing the efficacy and safety of three inguinal lymphadenectomies in penile cancer: (A) operative time, (B) blood loss, (C) drainage time, (D) hospital stay, (E) the lymph node number of lymphadenectomy, the incidence of (F) all adverse events, (G) minor complication, (H) major complication, (I) wound infection, (J) lymph edema, (K) lymphocele, and (L) recurrence. The size of each node represents the number of participants, while the thickness of the line represents the number of studies that directly compared the two interventions. O, open inguinal lymph node dissection; R, robot-assisted video-endoscopic inguinal lymph node dissection; V, video-endoscopic inguinal lymph node dissection. Table 1 - The outcome comparing the efficacy and safety of three inguinal lymphadenectomies in penile cancer by Bayesian network meta-analysis: (A) operative time, (B) blood loss, (C) drainage time, (D) hospital stay, (E) the lymph node number of lymphadenectomy, the incidence of (F) all adverse events, (G) minor complication, (H) major complication, (I) wound infection, (J) lymph edema, (K) lymphocele, and (L) recurrence. A B C VEILND VEILND VEILND −7.47 (−41.42, 25.03) RAVEIL −23.44 (−52.64, 5.62) RAVEIL −5.35 (−12.72, 0.98) RAVEIL 25.20 (11.40, 39.01) 32.67 (−0.02, 66.72) OILND −24.26 (−33.83, −14.93) −0.76 (−28.44, 26.67) OILND −2.17 (−4.01, −0.22) 3.19 (−2.84, 10.35) OILND D E F VEILND VEILND VEILND 2.91 (−0.26, 6.14) RAVEIL −1.92 (−4.00, −0.41) RAVEIL 0.45 (0.19, 1.18) RAVEIL −4.38 (−5.43, −3.38) −7.28 (−10.70, −3.98) OILND −0.15 (−0.87, 0.37) 1.75 (0.38, 3.64) OILND 0.22 (0.14, 0.32) 0.48 (0.20, 1.01) OILND G H I VEILND VEILND VEILND 0.72 (0.14, 6.41) RAVEIL 0.24 (0.01, 9.25) RAVEIL 0.27 (0.02, 2.44) RAVEIL 0.39 (0.14, 0.99) 0.54 (0.08, 2.11) OILND 0.07 (0.01, 0.59) 0.30 (0.02, 4.46) OILND 0.17 (0.06, 0.39) 0.65 (0.07, 5.70) OILND J K L VEILND VEILND VEILND 0.29 (0.00, 16.04) RAVEIL 1.22 (0.37, 3.51) RAVEIL 0.97 (0.26, 3.85) RAVEIL 0.42 (0.07, 1.76) 1.46 (0.03, 68.04) OILND 0.98 (0.60, 1.50) 0.81 (0.3, 2.31) OILND 0.79 (0.51, 1.23) 0.81 (0.2, 3.16) OILND The bold values are represent statistically significant results. The significance level is based on a p-value of less than 0.05 in the two-sided test.OILND, open inguinal lymph node dissection; RAVEIL, robot-assisted video-endoscopic inguinal lymph node dissection; VEILND, video-endoscopic inguinal lymph node dissection. Figure 2: Cumulative ranking probability plots for the efficacy and safety of three inguinal lymphadenectomies in penile cancer: (A) operative time, (B) blood loss, (C) drainage time, (D) hospital stay, (E) the lymph node number of lymphadenectomy, the incidence of (F) all adverse events, (G) minor complication, (H) major complication, (I) wound infection, (J) lymph edema, (K) lymphocele, and (L) recurrence. A darker color means a higher SUCRA ranking and a greater likelihood of an optimal solution. O, open inguinal lymph node dissection; R, robot-assisted video-endoscopic inguinal lymph node dissection; V, video-endoscopic inguinal lymph node dissection.In conclusion, VEIL demonstrated longer operative time, shorter blood loss, drainage days, and hospital stays, as well as a lower incidence of all AEs, major complications, minor complications, and wound infection compared to OILND. Our study supports the utilization of minimally invasive surgery, specifically VEIL, in treating patients with penile cancer. Furthermore, RAVEIL shows promising potential in terms of the number of inguinal lymph nodes dissected and disease recurrence. Future endeavors should focus on conducting large-scale, high-quality clinical studies to validate the utility of minimally invasive LND. Ethical approval Not applicable. Consent All authors consent to publication. Source of funding This study was supported by the National Key R&D Program of China (2023YFC3403200), the National Natural Science Foundation of China (82070784 and 81702536), and the Science & Technology Department of Sichuan Province, China (2022JDRC0040). Author contribution J.A., Z.H.: concept and design; J.A., Z.H., X.Y., J.L. and Y.T.: drafting of the manuscript; X.Y., J.L. and Y.T.: data curation; D.L., T.Z.: statistical analysis. J.A.: review and editing and supervision. All authors contributed to and revised the submitted version of the paper. Conflicts of interest disclosure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Research registration unique identifying number (UIN) Name of the registry: PROSPERO International prospective register of systematic reviews. Unique Identifying number or registration ID: CRD42024520478. Hyperlink to your specific registration (must be publicly accessible and will be checked): https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=520478. Guarantor Jianzhong Ai. Data availability statement The authors of this article will make available the raw data that supports the conclusions presented herein. Provenance and peer review Not applicable.

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