Total laparoscopic vs. conventional open abdominal nerve-sparing radical hysterectomy: clinical, surgical, oncological and functional outcomes in 301 patients with cervical cancer

Despite the wide spread of screening programs, cervical cancer still represents the fourth most common malignancy in women worldwide (being the second in developing countries) and the second most common cause of cancer-related deaths among women between 20 and 39 years old [1]. Surgery represents one of the mainstays of treatment in early-stage disease and radical hysterectomy (RH) with nodal dissection provides very good results in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2–IIA node-negative disease, with 5-year survival rates >90% [2].

RH is a challenging procedure and it has been traditionally related to a high incidence of peri-operative complications [3]. In addition, relevant long-term functional sequelae are associated with the procedure [4, 5, 6]. Iatrogenic denervation during radical surgery seriously interferes with pelvic function and results in considerable patients' distress and impaired quality of life (QoL), particularly in young women. In recent years, nerve-sparing RH (NSRH) has been proposed to reduce postoperative morbidity, without compromising oncological radicality [7, 8, 9]. The nerve-sparing concept was originally described by Kobayashi in 1960 [10], and subsequently described in different techniques by several authors [5, 11, 12, 13]. The results of the available series show that NSRH is equivalent to conventional RH in terms of survival, but it allows the preservation of pelvic function [14].

The advent of minimally invasive techniques has significantly improved the short-term outcomes of patients undergoing major gynecologic surgery, including RH, by enhancing recovery and decreasing pain and post-operative complications [15, 16]. However, recent publications (and particularly the Laparoscopic Approach to Cervical Cancer [LACC] trial) have raised serious concerns regarding the oncological safety of endoscopic surgery in cervical cancer [17, 18], describing a significant and alarming increase in the rate of recurrence. Despite the deep rethinking of the role of endoscopy in this setting, total laparoscopic RH has been adopted for years with the potential to increase the possibility to spare autonomic neural structures during the procedure: the image magnification offered by the laparoscope has markedly improved the possibility to identify and visualize thin structures, such as the pelvic autonomic nerves. Some studies have reported the outcomes of total laparoscopic NSRH (TL-NSRH), but a recent review on this issue has identified only 7 non-randomized series on a limited number of patients, comparing nerve-sparing vs. conventional procedures [14]. In addition, the authors of the review acknowledged that functional outcomes have been seldom described in depth in the available literature [14].

The aim of this study is to report our multi-center experience in terms of clinical outcomes and prognosis, comparing TL-NSRH vs. conventional open abdominal NSRH for early-stage or locally-advanced cervical carcinoma, performed before the publication of the LACC trial. A particular attention was paid to the description of functional results and patients' QoL.

The present analysis is a multi-institutional, retrospective series of consecutive patients who underwent class C1 (Querleu-Morrow classification) NSRH (performed by laparoscopy or by open abdominal surgery) [19] and systematic bilateral pelvic ± additional para-aortic lymphadenectomy for the treatment of carcinoma of the uterine cervix. The study involved patients from 4 Italian Institutions: Gynecologic Oncology and Minimally-Invasive Pelvic Surgery Unit of the IRCCS (Scientific Institute for Research, Hospitalization and Healthcare)—Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella (Verona), Endoscopica Malzoni, Center for Advanced Endoscopic Gynecologic Surgery, Avellino, Department of Obstetrics and Gynecology, DIMEC, S. Orsola Hospital, University of Bologna, and the Department of Obstetrics and Gynecology, University of Insubria, Varese. The protocol for this study was in line with the Strengthening the Reporting of Observational Studies in Epidemiology statement. From January 2007 to December 2012, all consecutive patients with early stage or locally advanced cervical cancer who underwent NSRH were enrolled. Inclusion criteria were: age >18 years, stage IA2–IIB, provision of written informed consent. Patients with positive history of malignancy and those with absolute contraindication to surgery were excluded. At the time of informed consent before surgery, each patient agreed to the use of her data in future clinical retrospective studies. Data on patient characteristics, tumor classification, pathology, surgical factors and follow-up were analyzed. Clinical staging of cervical carcinoma and preoperative evaluation were based on complete physical and rectovaginal examination, routine blood and urine analysis, chest radiography, transvaginal ultrasound. Cystoscopy and rectoscopy were performed only on specific indication; magnetic resonance imaging (MRI), or computed tomography (CT) were performed in the vast majority of cases (when clinical examination was ambiguous or inconclusive). The stage of the disease was determined by using the FIGO 2009 staging system. Patients were divided into TL-NSRH group and open abdominal (OA-NSRH) group, according to the type of surgical approach adopted. The surgical approach was chosen according to the availability or not of a surgical team with extensive experience in laparoscopic surgery.

A recent review and meta-analysis of studies comparing outcomes of nerve-sparing laparoscopic RH to those of standard minimally-invasive RH reported a total of 325 nerve-sparing procedures from 7 independent series [14]. The authors concluded that NSRH is more time-consuming but may be associated with similar oncological outcomes compared to non-nerve sparing radical procedures. The evaluation of functional outcomes in the included series was extremely poor and the level of evidence was low [14]. In this context, the recommendation of performing type C1 RH whenever possible, relies more on anatomical and logical considerations, rather than on scientific evidence.

The present study represents one of the largest available series of nerve-sparing laparoscopic vs. open abdominal radical hysterectomies for cervical cancer and it includes an extremely detailed and thorough evaluation of peri-operative surgical outcomes and post-operative pelvic function.

The main findings of our study are: first, the risk of surgical complications of this technically-challenging procedure is acceptable; we observed 25 (8.3%) cases of intra-/post-operative urinary tract lesions in the overall population, although our cohort included patients with locally-advanced disease, submitted to NACT [4, 26]. Second, we provide a large amount of data showing that the rate of pelvic dysfunction after this type of radical surgery is low, thus demonstrating that preservation of the neural autonomic fibers has actually a positive effect on patients' post-operative wellbeing and QoL. Third, the rate of pelvic dysfunction is lower when laparoscopic surgery is accomplished, rather than traditional open abdominal surgery. Fourth, the oncological outcomes and the survival rates of TL-NSRH well compare with the available series of non-nerve-sparing laparoscopic procedures [27]. Similar to the LACC trial [17], we observed a tendency towards earlier recurrences in the group of patients submitted to laparoscopic surgery. However, with extended follow-up, the DFS curves of laparoscopic and open abdominal procedures move closer and finally overlap. On the other hand, OS was quite similar between the 2 groups in our series.

In the era post-LACC trial, the presentation of series of laparoscopic radical hysterectomies for cervical cancer, may be unpopular. However, some considerations have spurred us to publish the present article: 1) one of the main criticisms against the LACC trial is the inclusion of many centers with not renowned experience in minimally invasive techniques for cervical cancer; the criterion for including a center in that trial was the evaluation by a central committee of 2 unedited videos of endoscopic RH. The operators involved in laparoscopic procedures have a solid background in advanced minimally-invasive surgery. 2) The data presented have been collected before the publication of the LACC study. 3) Our oncological data well compare with an important historical series by Landoni et al. [2] describing the use of open surgery in cervical cancer, and including more favorable cases. The very good results of open surgery in the LACC trial appear unprecedented and difficult to be replicated. 4) Our thorough analysis of the outcomes of nerve-sparing surgery performed on a considerable number of patients may be helpful for pre- and post-operative counseling and could be at least partly independent of the type of surgical approach used. 5) The observation that urinary incontinence, voiding difficulties and fecal constipation, although generally low, were more common among patients submitted to OA-NSRH may imply an important finding, i.e. that the magnified view of the laparoscope may allow a more subtle and precise identification of the pelvic autonomic fibers, with a more efficient sparing of nerves and function.

It is well accepted that bladder, colorectal and sexual dysfunction affect the long-term recovery of patients undergoing RH for cervical cancer. This type of outcome depends on the disruption of the pelvic autonomic nerves during resection of the lateral and posterior parametria. Specific steps of RH may cause surgical neuro-ablation of autonomic fibers leading to or belonging to the pelvic plexus (PP). The injured neural structures during RH are: the superior hypogastric plexus (ortho-sympathetic) during presacral and para-aortic lymph-node dissection; the hypogastric nerves (HNs - ortho-sympathetic) during resection of uterosacral and rectovaginal ligaments; the pelvic splanchnic nerves (PSNs; parasympathetic) and the PP (mixed ortho- and parasympathetic) during resection of the cardinal ligament in the lateral part of the parametrium and during resection of the vesicovaginal ligaments and paracolpia in the caudad anterior part of the parametrium [28].

Thanks to the enhanced view of the laparoscopes, the performance of nerve-sparing surgery using a minimally-invasive approach appears extremely precise and allows a careful and respectful dissection of the “pars vasculosa” from the “pars nervosa” of the parametrium [29, 30], which can be resected with an adequate oncological radicality but at the same time sparing the visceral efferent branches of the PP and finally resulting in lower bladder, ano-rectal and sexual dysfunction.

In our experience, the first step for a safe NSRH is the knowledge of the anatomy of the female pelvis and pelvic ligaments. To better identify neural fibers and surgical landmarks, avascular spaces are routinely developed: typically, the medial and lateral (Latzko's space) pararectal spaces are dissected, in order to achieve different dissection planes, leading to the Deep Uterine Vein and to the origin of the parasympathetic PSN at the sacral roots [26]. According to the series by Ercoli et al. [30], it is anatomically possible to identify 3 main groups of visceral efferent fibers, leaving the PP, directed to the target viscera:

Regardless of the surgical approach, the accomplishment of an adequate NSRH mandates to reveal the PP with its efferent groups of fibers and to transect only the uterine branches arising from the cranial efferent bundle. In this way, bilateral preservation of HN, PSN and medial and anterior efferent bundles from the PP, is achieved [6, 30, 31].

In recent years, the importance of NSRH in cervical cancer has become even more evident, considering that more than 54% of women diagnosed are younger than 50 years of age [1]. Since 5-year survival has been reported between 88%–97% after RH for early stage node-negative cervical cancer [2, 17, 32], the definition of procedures with a lower impact on post-operative QoL appears crucial. Unfortunately, the main limitation of the available studies on this issue is the lack of adequate analysis of the post-operative pelvic dysfunction and the short follow-up period, particularly in terms of QoL and functional outcomes.

Concerning bladder function, our study shows that 12–24 months after the operation no patients in the laparoscopic group and only 5 in the overall cohort complained of complete urinary retention: a prolonged period of follow-up is therefore essential to detect the real bladder dysfunction rates after RH [33]. This aspect may reflect the fact that nerve-sparing radical procedure actually spare at least some visceral fibers of the PP, even in cases in which denervation seems evident. However, in case of partial neural damage, a long time may be required by the “survivor” visceral fibers of the PP for sprouting and increasing their connections with the target viscera.

As previously described, rectal dysfunctions can occur after laparoscopic RH [34]. Internal and external sphincters contract by coordination of parasympathetic and sympathetic fibers, while defecation involves the interaction of voluntary and involuntary pathways. It is not easy to quantify the grade of the most common bowel functional complaints, such as constipation, incomplete evacuation, tenesmus, or diarrhoea. However, some studies show a negative effect of RH on bowel function (higher volumes of rectal distension to elicit the anorectal inhibitory reflex, slow transit constipation, tenesmus, diarrhoea, faecal leakage, and flatus incontinence) [35]. Non-adequate radical mobilization of the rectum and radical resection of the dorsal and lateral paracervix can result in partial damage to the autonomic innervations of the rectum [31]. Long et al. [36] identified a total of 17 clinical trials in a recent systematic review and meta-analysis on NSRH. They reported only 2 studies that evaluated data about the time of recovery of the anorectal function: the time to first defecation was significantly shorter in the NSRH group in comparison with RH group [37, 38]. However, that review does not take into account the rate of incontinence, constipation and soiling, after RH [36]. Our results analyze in detail these aspects and show no case of “frequent” fecal incontinence at the last follow-up; 16.6% of patients complained of moderate constipation, with no impact on QoL after surgery. Of note, the majority of these patients reported constipation even before RH.

Considering sexual function, it is well known that after RH, women experience changes in their vaginal anatomy and function, resulting in sexual dysfunction for many patients. These changes include shortening and inelasticity of the vagina, resection of the paracolpia, and loss of ovarian function [7]. Of course, radiotherapy is a contributing factor to sexual dysfunction, with the associated loss of elasticity, vaginal dryness, shortening and consequent dyspareunia, due to fibrosis and vascular reaction of the irradiated tissues. Moreover, we must take into account also the psychological impact of a diagnosis of cervical cancer. In our series, only a small proportion of the women included were sexually active. This may be due in part to the fact that approximately one third of patients was >60 years and in part to the fact that the diagnosis of cervical disease had a detrimental impact on the sexuality of the women included. Overall, our data show good results in terms of sexual function and >70% of patients reported a satisfactory sexual life and unchanged libido. A recent study by Pieterse et al. [34] on a series of 229 patients (123 NSRH; 106 conventional RH) evaluated with a validated questionnaire) showed a significant sexual deterioration both at 12 and 24 months after surgery for the total study group (nerve sparing and classic RH). The complaints included absence of sexual activity, narrow or short vagina, pain during intercourse, little or no lubrication during sexual activity, and an overall unsatisfactory for sexual life. However, sexual activity increased significantly after 12 and 24 months of follow-up compared with the situation before the treatment. The authors concluded that there was not a clear difference in self-reported sexual life between groups of women treated with different surgical procedure (nerve sparing versus non nerve-sparing technique). Conversely, a previous study by our group shows that NSRH is associated with significantly better sexual outcomes, compared with the “classical” RH technique [7].

Regarding oncologic outcomes, we acknowledge that the concerns regarding minimally invasive surgery in cervical cancer represent nowadays a major barrier about its use in this malignancy. However, we believe that this argument deserves a thorough reconsideration and new data are needed to confirm or deny the detrimental effect of endoscopic techniques. In any case, our survival data are comparable with the majority of the available reports on cervical cancer and therefore we believe that they can be considered encouraging [2, 25, 39, 40]. In our opinion, final words on the role of minimally invasive surgery in cervical cancer are still to be pronounced.

Among the limitations of the present study we mention the retrospective design, the relatively small number of patients included and the inclusion of both early and locally-advanced stages submitted to neoadjuvant chemotherapy. The detailed collection of pre-, intra- and post-operative data, and the specific assessment of functional outcomes mitigate the possible reporting bias due to the retrospective nature of our analysis and represent the major strengths of this study. Regarding the inclusion of patients submitted to neoadjuvant treatment, a large, multicentre propensity-matched analysis by Ghezzi et al. [39] has shown that the use of laparoscopic surgery in this specific setting is adequate and provides optimal oncological results. Another possible limitation is the inherent selection bias: we noticed a higher proportion of patients with larger tumors in the open abdominal group; this raises the problem of a possible imbalance between the 2 groups both in terms of oncologic and functional outcomes. Moreover, the exclusion of the 7 patients who were refractory to NACT may have biased our survival analysis regarding locally-advanced disease. We also acknowledge that several factors, apart from the type of surgical approach, affect post-operative urinary and bowel function following NSRH, such as tumor size, urinary tract infection as well as individual surgeon's technique. To possibly correct for at least a part of these factors, it would be interesting to perform a study comparing pelvic function following NSRH with vs. without NACT. In conclusion, our study shows that TL-NSRH is a feasible, safe and effective procedure that conjugates adequate radicality with an improvement in post-operative functional outcomes. Irrespective of the surgical approach chosen (minimally-invasive or open) and outside of the aseptic setting of clinical trials, our data provide a reliable picture of the everyday clinical scenario in patients affected by early-stage as well as locally advanced cervical cancer. These data may serve as the basis for clinical counselling and future discussions on this relevant topic.

Supplementary Data 1

Operative technique

Supplementary Data 2

Questionnaire