Despite the large implementation of massive screening programs in occidental countries, cervical cancer (CC) still represents a major health issue, being the third most common malignancy among women younger than 39 years and the second most common cause of death for cancer among females between 20 and 39 years in the United States.1
Early-stage CC may undergo either surgery or radiation therapy, but radical hysterectomy represents the mainstay of treatment for CC, with an estimated curative rate accounting for 90% at 5 years.2 Traditionally, radical hysterectomy is related to a high rate of intraoperative and postoperative morbidity, including severe surgical complications and pelvic dysfunctions (eg, urinary, anorectal, and sexual dysfunctions).2–4 The introduction of minimally invasive (ie, laparoscopic and robotically assisted) surgery has modified the approach of CC patients.3–9 Albeit growing evidence showing that minimally invasive surgery has improved perioperative outcomes, literature is concordant in underlining that the route of surgical approach does not influence the occurrence of pelvic dysfunctions.8 Although pelvic dysfunctions are not life-threatening issues, they impact dramatically the patients’ quality of life.3,10
Pelvic dysfunctions are related to damage of pelvic plexus (sympathetic hypogastric and parasympathetic pelvic splanchnic nerves) during surgery. Hence, the preservation of pelvic autonomic nerves during surgery might minimize these complications. Several investigations evaluated the efficacy of nerve-sparing (NS) radical hysterectomy for the management of CC.11–16 Overall, they are in agreement in reporting a lower rate of pelvic dysfunctions in comparison to standard radical hysterectomy.4,7 However, only limited data comparing the safety, efficacy, and oncologic effectiveness of NS laparoscopic radical hysterectomy (LRH) is still available. Hence, we sought to evaluate the technical feasibility of NS-LRH and to compare perioperative, medium-term outcomes of NS-LRH and LRH.
Data of consecutive women undergoing primary surgical treatment for CC at the Gynecologic Oncology Unit of University of Insubria–Ospedale di Circolo, Fondazione Macchi (Varese, Italy), between May 2004 and December 2012, were analyzed. Data were collected prospectively in an institutional review board–approved database. All women included in the study gave written informed consent for data collection for research purpose.
Inclusion criteria were (1) age 18 years or older, (2) performance of laparoscopic radical surgery, and (3) at least 12 months’ follow-up after surgical treatment (only for alive patients).
Laparoscopic approach was introduced in our department for primary treatment of early-stage CC (stage IA2-IB1, IIA <4 cm) and for secondary treatment (after neoadjuvant chemotherapy) for locally advanced stage (stage IB2, IIA >4 cm, IIB) CC in 2004 and 2005, respectively. In August 2010, NS-LRH was introduced at our department after having acquired adequate background in conventional LRH. Laparoscopic approach was offered to all patients presenting with CC, unless specific contraindications existed. No patient refused laparoscopic surgery for anticipated difficulty of resection. In our institution, patients with locally advanced stage CC were randomized to have neoadjuvant chemotherapy plus surgery (LRH or NS-LRH) or concomitant chemoradiation therapy on the basis of an ongoing collaborative trail (European Organization for Research and Treatment of Cancer [EORTC] 55994 protocol).
Generally, surgical treatment included radical hysterectomy plus systematic pelvic lymphadenectomy, whereas para-aortic lymphadenectomy is limited for patients with bulky pelvic and/or para-aortic nodes or in case of suspicious lesions in the para-aortic area detected at preoperative radiological examination. Laparoscopic radical hysterectomies were classified in accord to classification adopted by the Gynecological Cancer Group of the EORTC.17 Types II and III radical hysterectomies were performed in accord to tumor diameter and stage of disease (type II radical hysterectomy was performed in patients with stage IA2 or stage IB1 and tumor diameter <2 cm). Detailed description of surgical technique is presented elsewhere.8 Briefly, type III NS-LRH was performed using a laparoscopic (using 5-mm ancillary trocars) or minilaparoscopic (using 3-mm ancillary trocars) technique. Before starting surgery, an intrauterine manipulator (RUMI System; Cooper Surgical, Trumbull, CT) in conjunction with a Koh cup (Koh Colpotomizer System; Cooper Surgical) was inserted vaginally.8 Pneumoperitoneum was created by a Verress needle introduced in the umbilicus, and carbon dioxide was inflated. Intra-abdominal pressure was kept at about 10 to 12 mm Hg, and Trendelenburg position was not exaggerated. A 5-mm laparoscope was introduced through the umbilicus in all cases. Three 5- or 3-mm ancillary ports were introduced under direct vision. Radical hysterectomy was started with coagulation and section of round and infundibulopelvic (or uterine-ovarian) ligaments, bilaterally. The anterior leaf of the broad ligament was opened; the uterovesical fold was incised; the bladder was mobilized and caudally reflected, and the paravesical spaces were entered. Subsequently, the pararectal spaces were developed. The uterine vessels were coagulated with bipolar energy and transected at their origin from the hypogastric arteries, bilaterally. The ureters were detached from their median attachments to the peritoneum and then unroofed to the point of their insertion into the bladder. An effort was made to avoid dissection of the tissue below the ureter to preserve innervation of the bladder. The vesicouterine ligament was transected, and the bladder was further mobilized inferiorly, with attention to preserve the nervous branches running from the inferior hypogastric plexus to the bladder. Then, the medial fibrous part of the uterosacral ligaments was separated from the nerves running in its lateral part. The medial part was resected, whereas the lateral was spared. The remaining parametria and paracolpos were divided, tailoring radicality on the basis of tumor stage. To ensure adequate vaginal margins, we used the Koh Colpotomizer cup to delineate vaginal fornices and transected the vagina by monopolar hook about 2 cm below the rim of the cup. The uterus was then extracted vaginally with the intrauterine manipulator still in place. Laparoscopic systematic pelvic lymphadenectomy is performed according previous description.8,18,19
No significant nonsurgical variations in patient care were observed during the study period. All surgical procedures were performed by the same team of skilled laparoscopists under the direct supervision of the senior author (F.G.).
Preoperative workup included pelvic bimanual examination under general anesthesia, abdominopelvic and thoracic computed tomography, and pelvic magnetic resonance imaging. Stage was attributed in accord to the International Federation of Obstetrics and Gynecology criteria.2 Interventions were performed under general endotracheal anesthesia. Women received a single dose of prophylactic antibiotic 1 hour before the surgery; antithrombotic prophylaxis was administered with low-molecular-weight heparin (30 days) and compression stockings (until full mobilization). Operative times were recorded from the first skin incision to the last suture (skin to skin). Blood loss was estimated from the contents of suction devices. Hospital stay was counted from the first postoperative day. Intraoperative complications included procedural organ damage and events for which intravenous medications (including blood transfusions) were needed. Postoperative complications were graded per the Accordion Severity Score.20 For the purpose of this study, only complications of grade 3 or greater that occurred within 6 weeks after surgery were analyzed.20
Patients were thoroughly counseled about the different possible treatments (radiotherapy vs surgery). In particular, in case of locally advanced stage, they were informed that the standard treatment is concomitant chemoradiation and that neoadjuvant chemotherapy + radical surgery represents an experimental option. Moreover, as aforementioned, our institution participated at the EORTC 55994 protocol, which randomized women to concomitant chemoradiation versus neoadjuvant chemotherapy + surgery.
Postoperative adjuvant therapy was given according disease and patient characteristics.8,18 Follow-up evaluations were planned monthly for the first 3 months, every 3 months for the first 2 years, then every 6 months for the first 5 years, and annually thereafter. Dates and sites of recurrence were recorded. Recurrences were classified in local (vaginal), regional (lymphatic pelvic and para-aortic), and distant (hematogenous, peritoneal, and other lymphatic).
Statistical analysis was performed with GraphPad Prism version 6.00 for Windows (GraphPad Software, San Diego, CA). Incidence of events among the groups was analyzed for statistical significance by using the Fisher exact test. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated for each comparison. Normality testing (D’Agostino and Pearson test) was performed to determine whether data were sampled from a Gaussian distribution. The t test and Mann-Whitney U test were used to compare continuous parametric and nonparametric variables, respectively. Disease-free and overall survival rates, within 3 years, were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. P < 0.05 was considered statistically significant.
During the study period, 96 patients had laparoscopic surgery for the management of CC. Laparoscopic radical hysterectomy and NS-LRH were performed in 63 patients (66%) and 33 patients (34%), respectively.
Patients’ baseline characteristics are reported in Table 1.
In the NS-LRH group, 19 patients (57.6%) had surgery via minilaparoscopy (using 3-mm instruments), whereas no patient in the LRH group had minilaparoscopy (P < 0.001). Patients undergoing NS-LRH had shorter operative time (210 vs 257 minutes; P = 0.005) and higher number of pelvic lymph nodes yielded (29 [range, 26–38] vs 22 [range, 8–49]; P < 0.001) than did patients in the control group. No between-group differences in parametrial width and vaginal cuff length were recorded (P > 0.05). No differences in blood loss and intraoperative and grade 3 or more postoperative complications were observed (P > 0.05). Perioperative results are listed in Table 2.
Nerve-sparing LRH was related to a lower catheterization time, voiding dysfunctions, and constipation rate than LRH (P < 0.05). Patients were catheterized with an indwelling Foley catheter for a median of 3.5 days (range, 2–7 days) and 5.5 days (range, 4–7 days) in NS-LRH and LRH groups, respectively (P = 0.01). After NS-LRH, 27 patients (82%) were dismissed with spontaneous voiding versus 37 patients (59%) after LRH (P = 0.02; OR, 0.3; 95% CI, 0.11–0.87). Voiding dysfunctions (including de novo urinary incontinence and urinary retention, occurred within the first 12 months after surgery) were lower in the NS-LRH than in the LRH group (1 [3%] vs 12 [19%]; P = 0.03). In addition, after LRH, 3 (5%) and 5 (8%) patients reported outlet constipation and dyschezia, respectively, whereas no anorectal issues were observed after NS-LRH (13% vs 0%; P = 0.04; OR, 10.2; 95% CI, 0.57–183.7). Sexually active women with available information about sexual functions were 23 patients (35%) and 27 patients (82%) undergoing LRH and NS-LRH, respectively. Three of 23 patients (13%) and none of 27 patients (0%) reported de novo dyspareunia (P = 0.09; OR, 9.3; 95% CI, 0.45-192.2). Survival outcomes were similar between NS-LRH and LRH (Table 3). No differences in 3-year disease-free (P = 0.72, log-rank test) and overall (P = 0.71, log-rank test) survival rates were recorded between groups (Fig. 1).
The present study showed that NS-LRH is a safe and feasible procedure for the treatment of CC patients. Our findings showed that NS-LRH is related to a reduction of pelvic (ie, urinary and anorectal) dysfunctions and to a reduced time of indwelling catheterization in comparison to LRH, without medium-term oncologic outcomes detriment.
Pelvic dysfunctions are common postoperative occurrences related to the risk-to-benefit ratio of standard radical pelvic surgery. The extirpation of the uterus along with radical resection of parametrial and paracolpium structures negatively affects bladder, anorectal, and vaginal/sexual functions due to the damage of autonomic pelvic nerves. Traditionally, these features were foregone and considered as a secondary issue in cancer patients. However, in the modern oncologic era, quality of life and health expectancies become paramount as a pure oncologic outcome. Hence, in almost all fields of oncology, we assisted to a shift from invasive and demolitive procedures to even less invasive and anatomy’s respectful approaches. Minimally invasive and NS techniques were used with the aim to improve quality of life.8,19 Several investigations suggested that the use of minimally invasive rather than open surgery and NS rather than non-NS approaches improve postsurgical patients’ outcomes.4,9 In particular, laparoscopy minimizes the effects of abdominal trauma, and the NS technique reduces the effects of iatrogenic denervation of the vagina and lower urinary and rectal tracts. However, only limited data about the use of these combined techniques (ie, NS-LRH) are still available.4,7,8,11–16 Searching the PubMed database (MEDLINE), we observed only few reports on the efficacy and medium-/long-term outcomes of NS-LRH.4,7,8,11–16 On December 21, 2013, PubMed was searched for English-language studies using the term “laparoscopic nerve sparing radical hysterectomy.” Table 4 reports the most representative studies describing outcomes of NS-LRH. Overall, they are in agreement to underline the technical feasibility of NS-LRH. In 2000, Possover et al13 reported encouraging results (in term of reduced pelvic dysfunctions) following laparoscopic-assisted radical vaginal hysterectomies performed with preservation of parasympathetic innervation of the bladder running in the cardinal ligaments. However, more than 10 years later, only few studies on this issue have been published. We can speculate that laparoscopists are reluctant to add other technical difficulties into a challenging procedure. In contrast with these assumptions, our data showed that the NS technique can be safely introduced, without neglect operative and postoperative outcomes in a setting in which surgeons are able to perform LRH.
The main limitation of the present investigation is related to the single-center study design. Moreover, owing to the relative small sample size, we were not able to adjust our results on the basis of patients’ characteristics. Not with standing, the prospective nature of the study and the inclusion of consecutive patients minimize the effects of possible selection bias.
In addition, 4 points of the present study deserve to be addressed: (1) the beneficial effects (in terms of operative time and number of nodes harvested) of NS-LRH are likely determined by the expertise of the surgeon because NS-LRH approach was introduced after having acquired adequate background in conventional LRH; (2) NS-LRH is a highly technically demanding procedure, and the same team of expert laparoscopists executed all the procedures; thus, our results are not reliable in centers that lack high endoscopic experience; (3) because NS-LRH was introduced later in comparison to LRH, patients in the NS-LRH group had a shorter follow-up in comparison to NS-LRH; however, to reduce this bias, we assessed survival outcomes within 3 years; and (4) the absence of standardized questionnaires and of preoperative and postoperative urodynamic testing needs to take into consideration when we analyze the occurrence of pelvic dysfunctions.3 However, the present study clearly showed a negative association between NS technique and the occurrence of pelvic dysfunctions.
In conclusion, the present study showed that in experienced hands NS-LRH is a safe and feasible procedure for the management of early-stage and locally advanced stage (following neoadjuvant chemotherapy) CC. The shift from LRH to NS-LRH might allow improving patients’ outcomes, because it is associated with a reduced characterization time and pelvic dysfunctions rate in comparison to standard LRH. Further attempts are needed to improve patients’ outcomes and minimize unnecessary demolitive procedures.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Radical hysterectomy; Nerve-sparing; Laparoscopy; Cervical cancer; Survival