www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 44), pp: 4598-4608 Research Paper Nerve-sparing versus non-nerve-sparing radical hysterectomy: surgical and long-term oncological outcomes Antonio Gil-Moreno1, Melchor Carbonell-Socias1, Sabina Salicrú1, Melissa Bradbury1, Ángel García2, Ramona Vergés3, Oriol Puig Puig1, José Luís Sánchez- Iglesias1, Silvia Cabrera-Díaz1, Javier de la Torre1, Natalia R. Gómez-Hidalgo1, Assumpció Pérez-Benavente1 and Berta Díaz-Feijoo1 1 Unit of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain 2 Department of Pathology, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Radiotherapy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain Correspondence to: Antonio Gil-Moreno, email: agil@vhebron.net, antonioimma@yahoo.es Sabina Salicrú, email: ssalicru@vhebron.net Keywords: cervical cancer; morbidity; recurrence; surgical treatment; survival Received: April 16, 2019 Accepted: June 29, 2019 Published: July 16, 2019 Copyright: Gil-Moreno et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Objectives: There are controversies regarding the long-term oncological safety of preservation of pelvic innervation during radical hysterectomy (RH). This study aimed to analyze the feasibility and safety of nerve-sparing radical hysterectomy (NSRH) for cervical cancer compared with non-NSRH following 17 years of experience in a tertiary cancer referral center. Materials and Methods: Between May 1999 and June 2016, all patients who underwent RH for cervical cancer were followed-up prospectively. Comparison analyses regarding surgical outcomes, complications, overall survival (OS), disease- free survival (DFS), and cancer-specific survival (CSS) were performed between patients treated with NSRH and non-NSRH. Results: A total of 188 patients were included (113 non-NSRH and 75 NSRH). The median follow-up was 112 months. Estimated blood loss and hospital stay were all significantly lower in the NSRH group. Overall intraoperative complication rate (p = 0.02) and need for transfusion (p = 0.016) were lower in the NSRH group. There were no differences in the median operation time, OS, DFS, CSS, or recurrence rates between the NSRH and non-NSRH group. Conclusions: Our study provides a wide perspective on the developments of nerve-sparing procedures for the management of women with early-stage cervical cancer. Our results suggest that NSRH is a feasible and safe procedure, with reduced morbidity outcomes. INTRODUCTION procedure [3]. This is mainly caused by the iatrogenic damage of the pelvic nerve plexus during surgery [4, 5]. Open conventional abdominal radical hysterectomy With the aim to provide an alternative surgical without nerve-sparing has been for many years the technique for these patients, the preservation of pelvic primary treatment for patients with early stage cervical innervation during radical hysterectomy (RH) was cancer [1, 2]. However, up to 25% of these patients will developed in Japan in the early 1920s [6]. This technique suffer severe reduction in their quality of life secondary evolved in the 1960s by adding the division of the to bladder, rectal, and sexual dysfunctions following the paracervix into its vascular and neural components, as www.oncotarget.com 4598 Oncotarget well as sparing the nerve bundle when sectioning the non-NSRH groups. Characteristics of the study population uterosacral ligament [7]. This technique, called nerve- and intra-operative data are presented in Tables 1 and 2. sparing RH (NSRH), was later expanded, allowing for the Estimated blood loss (EBL) and hospital stay (HS) preservation of the splanchnic nerves (parasympathetic were all significantly inferior in the nerve-sparing group, innervation), inferior hypogastric nerves (sympathetic whereas no differences were found in operative time (OT), innervation), and vesical branch of the lower hypogastric even when taking into account the surgical approach (open plexus during the dissection of the paracervical tissue. or MIS). Initially, the use of NSRH was limited because of Overall intra-operative complication rate (p = 0.02) the difficulties in the identification of the anatomical and the need for transfusion (p = 0.02) were significantly structures and the lack of data regarding its oncological lower in the NSRH group. The conversion rate to safety. In fact, it was not until 2008 that NSRH was laparotomy in the NSRH group was 0%, whereas for the first introduced in a standardized RH classification non-NSRH it was 3.92%. Morbidity data are detailed in [8]. Progressively, it was adopted by some European Table 3. centers [9–15] and over the last decade, it is has become The bladder and bowel function were investigated more commonly performed in the USA by gynecologic at one year after surgery. A total of 7 patients in the oncologists following the widespread use of robotic NSRH group and 22 patients in the non-NSRH presented technology. bladder and rectal functional-related complications. The However, as reflected by a recent systematic review, results are shown in Table 4. The incidence of urinary some groups still hesitate to introduce minimally invasive incontinence and loss of bladder filling sensation was surgery (MIS) for NSRH, arguing that the heterogeneity significantly lower in the NSRH group compare to in surgical techniques and the quality and volume of the non-NSRH group (1.3% vs. 3.5%; 1.3% vs. 5.3%, published literature prevents a high degree of certainty respectively) (p > 0.05). regarding both oncologic safety and quality of life In terms of oncologic outcomes, there were no improvement, compared with conventional RH [16]. differences in OS, disease-free survival (DFS), or We present the results from our institution of a recurrence rates between the NSRH and non-NSRH study with one of the longest follow-up duration to date groups (Figure 1). Of the 188 patients, 156 (82.98%) and analyze how the introduction of a nerve-sparing where alive and disease-free at the end of the study period, technique during RH has influenced the surgical and that is, 65 (86.67%) in the NSRH group and 91 (80.53%) oncologic outcomes of these patients. This study aimed in the non-NSRH group (p = 0.18). Recurrences are to analyze the feasibility and safety results of NSRH for specified in Table 5. Cancer-specific mortality rate was cervical cancer compared with conventional RH following 6% for the NSRH and 8.8% for the non-NSRH (p = 0.91). 17 years of experience in a tertiary cancer referral center. DISCUSSION RESULTS Evidence following publication of different series Between May 1999 and October 2006, a total of [17, 18] and recent meta-analysis [19, 20] has shown that 188 patients diagnosed with early-stage cervical cancer NSRH decreases bladder and rectal dysfunction without underwent RH in our institution. Of these patients, 113 compromising recurrence or survival rates compared with underwent a non-NSRH, 43 (38%) a Piver type II, and non-NSRH. This study represents one of the longer-term 70 (62%) a Piver type III RH. A nerve-sparing technique follow-up periods published to date in which the results was carried out in all radical hysterectomies performed for non-NSRH and NSRH are compared with respect to after October 2006 (n = 75): 30 (40%) with type B1 and surgical and oncologic outcomes. Although over 80% 45 (60%) with type C1. The decision to perform RH in the of nerve-sparing procedures were performed by MIS, five cases of locally advanced disease (IIB = 2 and IIB2- there were no differences in terms of surgical time when IIA2 = 3) was influenced by the patient’s characteristics compared with the non-NSRH group. Moreover, within the and preferences and agreed by the gynecology-oncology MIS group, NSRH presented with a significant reduction team. in OT. These results differ from those presented in a recent The median age was 48.2 (range, 25–77) years with meta-analysis [19, 21] in which both laparoscopic and a median body mass index of 26.1 (range, 18–40) kg/ abdominal routes presented greater surgical times in the m2. The median follow-up was 112 (range, 53.7–162.3) nerve-sparing group. This difference could be partially months. The predominant histologic type was squamous explained by the introduction of the RRH in our series, cell carcinoma (61.17%), followed by adenocarcinoma which presented with similar surgical times to ORH and (32.4%). Final pathology revealed 16 (8.51%) patients significantly lower times than LRH, contributing to an with tumors larger than 4 cm (pT1b2-T2a2) and 15 overall reduced OT in MIS. (7.98%) with microscopic parametrial involvement (pT2b) Similarly, in our series, NSRH showed significantly with no significant differences between the NSRH and inferior EBL compared to that of non-NSRH group. It www.oncotarget.com 4599 Oncotarget Table 1: Clinical and pathologic data in the NSRH and non-NSRH groups NSRH Non-NSRH All patients p n = 75 n = 113 n = 188 Age, years mean (SD) 47 (11.6) 49 (12.8) 48.21 (12.35) 0.27 BMI, median (range) 25 (18–37) 26 (18–40) 26.16 (18–40) 0.21 MS, n (%) 27 (36.49) 42 (37.7) 69 (36.9) 0.92 Previous abdominal surgery, n (%) 30 (52.2) 70 (59.2) 100 (53.1) 0.14 Parity, median (range) 2 (0–6) 2 (0–7) 2 (0–7) 0.52 Histological type, n (%) Squamous cell carcinoma 44 (58.6) 72 (62.8) 115 (61.2) 0.55 Adenocarcinoma 27 (36) 34 (30.1) 61 (32.4) Others 4 (5.3) 8 (7.06) 12 (6.38) Histological grade, n (%) G1 10 (13.3) 10 (8.85) 20 (10.6) 0.012 G2 44 (58.7) 56 (49.5) 100 (53.2) G3 21 (28) 33 (29.2) 54 (28.7) NS 0 14 (12.4) 14 (7.4) FIGO stage, n (%) 1A2 3 (4) 8 (7.08) 11 (5.85) 0.27 1B1 ≤ 2 cm 27 (36) 34 (30.1) 61 (32.45) 1B1 > 2 cm 34 (45.3) 63 (55.7) 97 (51.6) IIA1 6 (8) 8 (7.1) 14 (7.45) IIB 2 (2.67) 0 2 (1.06) IB2 & IIA2 3 (4) 0 3 (1.6) BMI, body mass index (kg/m2); MS, menopausal status; Non-NSRH, non-nerve-sparing radical hysterectomy; NSRH, nerve- sparing radical hysterectomy; NS, not specified; p, p value; SD, standard deviation. could be argued that the significant difference in EBL nerve-sparing techniques do not appear to be associated could be explained by the fact that most NSRH were with smaller surgical resections in laparoscopic nor open performed by MIS. The reduction in EBL with this procedures. approach is consistently reported in most studies [22]. In our series, we found significant differences in However, the reduction in EBL is persistent even when vascular injury rates and patients requiring transfusion, comparing NSRH with non-NSRH within each of the in favor of the NSRH group. Although our study supports surgical approaches (MIS and ORH). In this regard, the the evidence presented in a recent meta-analysis [19] accumulative experience of the surgical team as well as regarding the reduction in intraoperative complications the progressive introduction of vessel sealer devices could associated with nerve-sparing techniques, we should partially explain the results [23]. reconsider the fact that most of the nerve-sparing The number of excised pelvic nodes in our series procedures were performed by MIS, which by itself is similar to that previously reported in the literature, is related to fewer intra-operative complications [25]. with no differences between the NSRH and non-NSRH We decided to consider transfusion as a complication groups. In two published meta-analysis [19, 24] in which because it marked a differential management of the NSRH is compared to non-NSRH, the number of excised patients and could be related to greater postoperative pelvic nodes is not considered a meaningful variable of morbidity. comparison. Regardless, we consider that these results The NSRH technique improved all the urinary would support the oncologic safety of the nerve-sparing symptoms (frequent urination, urinary incontinence, technique. difficulty emptying and bladder sensation), which could In our series, the total paracervix volume resected be due to the complete preservation of autonomic nervous was similar between the NSRH and non-NSRH groups, structure that controls the bladder in the nerve plane regardless of the surgical approach. These results are [26]. Moreover, the full recovery of urinary function similar to those presented by other groups [24, 25]. Thus, usually take approximately one year after radical surgery; www.oncotarget.com 4600 Oncotarget Table 2: Operative data NSRH Non-NSRH All patients Surgery, n (%) p n = 75 n = 113 n = 188 Type of RH, n (%) NA B1 RH 30 (40) C1 RH 45 (60) Type II RH 43 (38) Type III RH 70 (61) Ovarian preservation, n (%) 28 (37.3) 43 (38.05) 71 (37.1) 0.88 Sentinel node procedure, n (%) 53 (71) 68 (60.1) 121 (64.4) 0.87 Approach, n (%) LRH 39 (52) 51 (45.1) 90 (47.9) ORH 14 (18.6) 62 (54.8) 76 (40.4) RRH 22 (29.3) 0 22 (11.7) LRH+RRH (MIS) 61 (81.3) 51 (45.1) 112 (59.7) Extracted pelvic nodes, median (range) 20 (8–49) 20 (5–52) 20 (5–52) 0.95 ORH 21.5 (9–49) 20.5 (5–-52) 0.80 MIS 20 (8–37) 18 (8–51) 0.25 Patients with positive pelvic nodes, n (%) 13 (17.33%) 11 (9.75%) 23 (12.77%) 0.126 Mean total parametrial volume, cm3 (SD) 18.91 (9.62) 20.26 (10.47) 19.68 (10.1) 0.41 Mean operative time, min. (SD) 261 (47.98) 269 (50.7) 266.08 (49.68) 0.27 ORH 239.64 (53.65) 246.05 (38.78) 0.74 MIS 266.19 (45.56) 297.55 (49.37) 0.002 Mean blood loss, cm3 (SD) 199.32 (191.81) 460.93 (276.29) 357.41 (277.23) < 0.0001 ORH 317.86 (302.94) 544.35 (309) 0.0006 MIS 171.67 (145.56) 359.51 (188.09) 0.0000 Hospital stay (HS), median (range) 3 (2–12) 8 (2–33) 5 (3–10) < 0.0001 ORH 6 (3–12) 9 (5–33) 0.0000 MIS 3 (2–7) 5 (2–32) 0.0000 LRH, laparoscopic radical hysterectomy; NA, not applicable; NSRH, nerve-sparing radical hysterectomy; Non-NSRH, non- nerve-sparing radical hysterectomy; ORH, open radical hysterectomy; RRH, radical robotic hysterectomy; SD, standard deviation. according to recent publications [27] we found that the results [28]. Our oncologic results in terms of OS, DFS, NSRH group presented less urinary incontinence, loss of recurrences and cancer-specific mortality rates were bladder filling sensation and straining of urinate compare similar between the two groups, as suggested by previous to non- NSRH group although it did not reach statistical studies [24]. significance. We know that there are some limitations in our Our results show an association between NSRH study. First, it was conducted in a single centre and, and significant HS reduction. Morbidity reduction therefore, it could be subject to biases derived from the related to autonomic nerve plexus preservation as well technology and expertise available in our centre. Second, as progressive improvement of the surgical technique we had few patients to generate conclusive results in some with accumulated experience may account for these aspects of the study. And third, as the study was carried results. Nevertheless, we consider that the changes in out for more than 17 years there were unavoidable changes the peri-operative management of these patients, with in the methodologies used. In contrast, one of the strengths the progressive introduction of enhanced recovery after of this work is that it reflects our long-term experience in surgery (ERAS®) in our Gynecology Oncology unit in these surgical techniques and the long follow-up of a large recent years, probably played a fundamental role in these number of patients. www.oncotarget.com 4601 Oncotarget Table 3: Morbidity data Intraoperative complications ≤ 30 Days complicationsa Patients n = 34 n = 37 Nerve- 2 vesical lesions (suture and prolonged Grade II: n = 4 sparing urinary catheter) 2 urinary infections 1 acute urine retention 1 abdominal wall infection 1 ureteral section (suture) Grade IIIa: n = 1 3 blood transfusions lymphocele (drainage) 75 Grade IIIb: n = 5 2 vaginal dehiscences (vaginal suture without complications) 1 urinoma secondary to ureteral lesion (secondary to sutured ureter) (laparotomy ureteroneocystostom) 2 abdominal eviscerations Non-nerve 1 vesical perforation Grade II n = 21 sparing 2 ureteral sections (ureteroneocystostomy) 7 urinary infections 6 acute urine retention 5 ileus 3 abdominal wall infections 2 conversions to laparotomy (due to Grade IIIb: n = 5 ureteral section) 4 vaginal dehiscence (vaginal suture)1 urinary 1 anaphylactic shock secondary to fistula Isosulfan Blue injection for SLN identification 113 1 intestinal perforation Grade V: n = 1 Progressive multiorgan dysfunction secondary 1 obturator vein lesion (bipolar to massive intraoperative bleeding due to coagulation and compression) vascular lesion 1 cava vein lesion (suture) 1 left internal Iliac vein lesion (Tissucol™ -Baxter AG, Vienna, Austria- and compression) 1 external iliac vein lesion (suture) 17 blood transfusions Treatments within parentheses in italics. SLN, sentinel lymph node. a Clavien-Dindo Scoring System [20]. Table 4: Bladder and rectal function 12 months after surgery NSRH (n = 75) Non-NSRH (n = 113) p-value Urinary incontinence 1 (1.3%) 4 (3.5%) 0.81 Loss of bladder filling sensation 1 (1.3%) 6 (5.3%) 0.48 Straining of urinate 3 (4%) 8 (7%) 0.76 constipation 2 (2.6%) 4 (3.5%) 0.55 Total 7 (9.3%) 22 (19.4%) 0.06 www.oncotarget.com 4602 Oncotarget Figure 1: Survival curves comparing NSRH with non-NSRH. www.oncotarget.com 4603 Oncotarget Table 5: Recurrence data NSRH Non-NSRH Total n = 75 n = 113 n = 188 Recurrence location, n (%) Vaginal 3 (23.08%) 3 (21.43%) 6 (21.4%) Pelvic wall 5 (38.46%) 4 (21.43%) 9 (32.1%) Peritoneal 1 (7.69%) 1 (7.14%) 2 (7.1%) Supraclavicular lymph node 1 (7.69%) 0 1 (3.5%) Distant metastasis 2 (15.38%) 1 (7.14%) 3 (10.7%) Pelvic wall + vaginal 0 3 (21.43%) 3 (10.7%) Pelvic wall + umbilical 0 1 (7.14%) 1 (3.5%) Peritoneal + inguinal lymph node 0 1 (7.14%) 1 (3.5%) Hepatic + vaginal 0 1 (7.14%) 1 (3.5%) Pelvic wall + distant metastasis 1 (7.69%) 0 1 (3.5%) Time of recurrence, n (%) < 1 year 4 (30.8%) 6 (40%) 10 (35.7%) < 2 years 7 (53.8%) 12 (80%) 19 (67.9%) < 5 years 10 (76.9%) 14 (93.3%) 24 (85.7%) Total, n (100%) 13 (100%) 15 (100%) 28 (100%) MATERIALS AND METHODS Treatment Patients Nerve-sparing technique was first introduced in our institution in October 2006. Procedures performed before The study was approved by our institutional review 2006 were classified following the 1974 RH classification board (PR (AMI) 23/1999) and in accordance with the [30], and after the introduction of nerve-sparing technique, Helsinki Declaration. All women provided informed the new 2008 classification [15] was used accordingly. consent for the surgical procedure, as well as for the Patients with FIGO stage IA2 or IB1 with tumor size ≤ 2 recording and analysis of all relevant clinical data. cm underwent proximal or modified RH (Piver type II) Between May 1999 and June 2016, all patients or type B1. Patients with FIGO stage IB1 with a tumor who were diagnosed with International Federation of mass less than 2 cm on physical examination but with a Gynecology and Obstetrics (FIGO) stage IA2-IB1-IIA1 larger mass on magnetic resonance imaging and those cervical cancer who underwent an RH as first treatment with a tumor mass larger than 2 cm underwent distal RH at our institution were included in the study. Pregnant technique (Piver type III) or type C1. women and those patients who had received previous The decision to perform a laparoscopic or open chemotherapy or pelvic radiotherapy were excluded from approach depended on the patient’s characteristics together the study. with the surgeons’ and patients’ preferences. In 2009, with All patients had their initial pathologic diagnosis our center’s acquisition of one of the first robotic surgery confirmed at our institution, following a cervical punch devices in our country, robotic radical hysterectomy (RRH) biopsy or a cone biopsy. Patients were staged according was progressively introduced for performing RH. General to the 2009 cervical cancer FIGO classification. exclusion criteria for the MIS approach (laparoscopic or Patients undergoing surgery before 2009, which had robotic) include severe cardiorespiratory disease preventing been initially staged according to the 1988 FIGO a Trendelenburg position, enlarged uterus over 12 classification, were restaged according to the new gestational weeks, body mass index of 40 kg/m2 or higher, 2009 staging system [1, 2]. In all patients, magnetic and age 80 years or older. The decision to use robotic resonance imaging was performed prior to surgery. The surgery was also limited by the availability of the device. surgical complications were classified according to Dindo et al. [29]. Surgical technique Information of interest was recorded prospectively from the time of surgical indication to the last follow-up In the nerve-sparing technique (radical hysterectomy date recorded at the time of study closure. C1), the inferior hypogastric nerves, pelvic splanchnic www.oncotarget.com 4604 Oncotarget nerves, and inferior hypogastric plexuses with efferent system. The minimally invasive approach can facilitate nerves to the bladder and vagina are preserved, as this surgical procedure in comparison to the laparotomic opposed to the conventional technique. The key to approach. optimal nerve preservation is the systematic identification Three fundamental steps should be kept in mind of the anatomical structures of the autonomic nervous when developing the NSRH technique (Figure 2). The Figure 2: Nerve-sparing radical hysterectomy: Key steps. R right side view of the pelvis; L left side view of the pelvis; B bladder; HN inferior hypogastric nerve; HP inferior hypogastric plexus; HV hypogastric vein; O Okabayashi space; OM intern obturator muscle; ON obturator nerve; P paracervical tissue; PR pararectal space; PV paravesical space; R rectum; SN pelvic splanchnic nerve (S2-S3); U ureter; US uterosacral ligament; UV deep uterine vein stump (hemolock); V vagina; VA superior vesical artery; VP vesical plexus; VV inferior and middle vesical veins; Y Yabuki space. (A) The pelvic splanchnic nerves are seen joining the HP in a perpendicular fashion, after sectioning the UV. (B) Distal fibers of the HP run toward the vagina and bladder along the dorsal vesicouterine ligament and the lateral wall of the vagina. (C) Pelvic autonomic nerves, nerve-sparing radical hysterectomy. (D) Isolation and preservation of the HN during dissection of the US and the Okabayashi space. (E) Dissection of the US and the Okabayashi space. (F) Dissection of the ureteral tunnel and Yabuki space. www.oncotarget.com 4605 Oncotarget first step is to isolate and separate the deep uterine expansion of NSRH surgery has been properly addressed vein from the lower hypogastric plexus. After sentinel by the long follow-up period in this study. Properly lymph node (SLN) identification and subsequent pelvic designed prospective clinical trials about the subject would lymphadenectomy, the paravesical and pararectal spaces offer stronger evidence to support NSRH as the preferred are dissected. This isolates the paracervical tissue approach for early-stage cervical cancer. that includes the uterine artery and the superficial and deep uterine veins. When dissecting, coagulating, and Abbreviations sectioning the deep uterine vein, ventral branches of the splanchnic nerves (S2-S3-S4) can be observed along its CSS: Cancer-specific survival; DFS: Disease- path toward the lower hypogastric plexus (Figure 2A–2C). free survival; EBL: Estimated blood loss; FIGO: The second step includes the isolation and preservation Federation of Gynecology and Obstetrics; HS: Hospital of the inferior hypogastric nerves, which are attached to stay; LRH: Laparoscopic radical hysterectomy; MIS: the splanchnic nerves in the inferior hypogastric plexus, Minimally invasive surgery; NSRH: Nerve-sparing during dissection of the uterosacral ligament and the radical hysterectomy; ORH: Open radical hysterectomy; Okabayashi space (Figure 2D, 2E). Finally, the third step OS: Overall survival; OT: Operative time; RH: Radical involves the preservation of the efferent bladder branches hysterectomy; RRH: Robotic radical hysterectomy; SLN: of the inferior hypogastric plexus, on the posterior leaf Sentinel lymph node. of the vesico-uterine ligament, during dissection of the Yabuki space. Visualization of the middle and lower vesical veins helps preserve these efferent branches Author contributions (Figure 2F). The surgical technique of open radical hysterectomy Conception and Design of Study: AGM, Data (ORH), laparoscopic radical hysterectomy (LRH), and RRH collection: AGM, MC, SS, MB, AG, RV, SC, JT, Data with and without a nerve-sparing approach together with the analysis and interpretation: AGM, MC, SS, JLSI, SLN identification procedure used by our group has been Responsible surgeon or imager: AGM, AG, RV, OP, SC, described in detail in previous publications [14, 31, 32]. APB, Statistical analysis: MC, MB, JLSI, SC, Manuscript preparation: AGM, MC, SS, NRGH, AP, BDF, Patient Statistical analysis Recruitment: AGM, AP, BDF. Data are expressed as mean and standard deviation ACKNOWLEDGMENTS for normally distributed variables and as median and range of variables whose distribution departed from We thank Editage, for the assistance in editing this normality. Variables were tested for normality using the manuscript. Kolmogorov-Smirnoff test. For qualitative variables, chi- square and Fisher’s exact test were used. For quantitative CONFLICTS OF INTEREST variables, analysis of variance or Kruskal-Wallis test was used. Kaplan-Meier survival analyses were performed to Nothing to disclose. estimate overall survival (OS), recurrence-free survival, and cancer-specific survival. Differences in the probability FUNDING of survival according to the surgical procedure were compared using the log-rank test. Statistical significance None. was set at p < 0.05. 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