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Abstract
Objectives Pelvic side wall infiltration by gynecological malignancies has been considered for a long time an absolute contraindication to curative resection. The development of the laterally extended endopelvic resection (LEER) has challenged this surgical paradigm. Although the LEER has been standardized in open surgery, only small studies have been published about its endoscopic feasibility. The objective of this study is to analyze the safety of LEER in patients with gynecological malignancies involving the pelvic side wall.
Methods We retrospectively evaluated a consecutive series of patients who underwent a laparoscopically modified LEER between July 2014 and November 2018. This indicated gynecological tumors involving the pelvic sidewall and surgeries were conducted in two Italian institutions. All patients underwent pre-operative CT scan or PET to evaluate for distant metastases. Patients without suspicioun of distant metastasis underwent pelvic MRI and examination under anesthesia to establish the resectability of the disease and concomitant diagnostic laparoscopy to exclude intraperitoneal dissemination. All women with disease-free interval <6 months, and/or performance status >2 ECOG were excluded. Type of resection was defined based on the status of the pathologic margins: R0, microscopically negative (free margin <5 mm); R1, microscopically positive; and R2, macroscopically (grossly) positive. Disease-free survival was calculated from the date of primary surgery to the time of recurrence. Overall survival was defined as the time from primary surgery to death.
Results Overall, 39 patients underwent a laparoscopic LEER and 18 (46.2%) patients were eligible for a laparoscopic approach. Laparoscopic LEER was performed as primary treatment for newly diagnosed tumors in eight patients (44.4%), and for recurrences in the other 10 patients (55.6%). No laparotomic conversions were registered. R0 resection was achieved with negative margins in all patients. The median operative time was 415 min (range, 285–615), median estimated blood loss was 285 mL (range, 100–600), and the median length of hospital stay was 10 days (range; 4–22). Only four patients (22.2%) needed blood intraoperative transfusion. In seven patients (38.9%), post-operative admission to intensive care unit was required. There were three (16.7%) intraoperative complications, all managed laparoscopically. In total there were six (33.3%) major postoperative complications: three patients (16.7%) experienced moderate hydronephrosis with normal renal function, which required temporary placement of nephrostomy; one patient (5.6%) had permanent urinary retention; and two patients (11.1%) had a reoperation, one for post-operative hemoperitoneum and another for complete vaginal cuff dehiscence.
Discussion Laparoscopic LEER can be safely performed by experienced laparoscopic surgeons, in carefully selected patients with gynecological malignancies involving the lateral pelvic side wall, even for those in which a bladder and rectum sparing surgery appears possible. Further larger prospective trials are needed to evaluate the oncological and the long-term functional outcomes.
- gynecology
- pelvis
- surgical oncology
- laparoscopes
- genital neoplasms, female
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Highlights
Laparoscopic LEER procedure may be performed in patients with gynecological malignancies involving the pelvic side wall.
Laparoscopic LEER procedure may be considered an alternative to the open approach and rates of complete tumor resection are favorable.
The rate of intraoperative complications was 16.7% and of major postoperative complications was 33%.
INTRODUCTION
Lateral pelvic sidewall involvement by gynecological tumors has been considered an absolute contraindication to curative resection.1 Furthermore, in a large group of women the involvement of the pelvic sidewall occurs at the time of relapse after primary or adjuvant pelvic radiation. Therefore, radiation therapy administered on the same site does not represent a therapeutic option, and chemotherapy is not an effective strategy due to the reduced drug penetration in the tumor site.2 3 In an effort to provide a systematic surgical approach to achieve complete resection in this subset of patients, laterally extended endopelvic resection (LEER) based on the ontogenetic compartment theory, has been proposed.4 5 Although LEER was originally described for recurrent tumors, it has also been proposed for locally advanced cancer.6 LEER consists in the extension of the pelvic resection plane to the medial portion of the acetabulum, obturator membrane, sacrospinous ligament, sacral plexus and piriformis muscle, with complete removal of the internal iliac vascular compartment.7 8 The high rate of complete resection (R0) and the encouraging oncological outcomes obtained, have suggested LEER as an attractive therapeutic option for the management of patients with pelvic sidewall involvement.9 10
For more than a decade, the laparotomic route has been considered the only option to successfully complete this ultra-radical surgery, but the advantages of laparoscopy related to improved visualization of anatomic structures located deep in the pelvis and reduction of intraoperative blood loss, have challenged this paradigm.4 However, to date only a small report including three cases has been published on the feasibility of LEER through minimally invasive surgery.11 Therefore, although LEER has been standardized in open surgery, its feasibility and safety by laparoscopy is still under investigation. With the aim of addressing this specific issue, we analyzed the feasibility and safeness of the laparoscopically-modified LEER in a consecutive series of patients with gynecologic malignancies involving the pelvic side wall.
Methods
Data of patients who underwent a LEER procedure for gynecological malignancies involving the pelvic side wall from July 2014 to November 2018 were retrospectively retrieved from the oncological databases of two institutions: Department of Gynecologic Oncology, University of Palermo; and Division of Gynecologic Oncology, Fondazione di ricerca e cura Giovanni Paolo II, Catholic University of the Sacred Heart of Campobasso. These oncological databases are research-quality datasets that are prospectively maintained and regularly updated by trained residents under direct consultant supervision. Informed consent was obtained from all patients for the entry of data regarding treatment and oncologic outcome in our research databases. The study was approved by the Local Ethics Committee of both institutions (252 CIVICO 2019). Surgery was performed in both centers by the same operator (VC). Demographic, clinical, and pathologic data were retrieved from medical records. As per institutional policy, all tumor histologies were reviewed prior to surgery, and no additional pathology review was performed for the purpose of this study.
All patients underwent pre-operative chest-abdomen CT scan or positron emission tomography (PET) to evaluate for distant metastases. Patients without distant metastasis, underwent pelvic MRI and physical examination under anesthesia to establish resectability of the disease, and concomitant diagnostic laparoscopy was performed to exclude intraperitoneal dissemination. Patients with positive aortic nodes at pre or intra-operative examination were considered unsuitable for laparoscopic LEER. Complete resection was considered possible in women with visceral disease fixed to the pelvic side wall but not infiltrating the parietal endopelvic fascia: therefore, without suspicioun of involvement of the neurovascular structures of the sciatic foramen. Furthermore, patients with a mass beyond the pelvic cavity, infiltrating the iliopsoas muscle were not considered suitable for laparoscopic LEER. In fact, although the resection of these anatomical structures has been previously described,12 13 their involvement, due to the extra-compartmental spreading, represents an exclusion criterion for LEER.10 In patients with persistent or recurrent disease, previously treated with radiotherapy, or with any curative therapeutic option alternative to extended pelvic surgery were excluded. In the remaining patients, the indication for ultra-radical surgery was discussed and approved in a multidisciplinary institutional tumor board. Indeed, according to our policy, a priori, all women with disease-free interval <6 months, and/or with a performance status >2 according to ECOG (Eastern Cooperative Oncology Group) were excluded.14
Considering the innovative nature of the technique, patient selection was very strict, and inclusion criteria for laparoscopy were: tumor size <10 cm, body mass index (BMI) <35 kg/m2 and absence of tenacious adhesions syndrome at preliminary diagnostic laparoscopy. Selection criteria are shown in online supplementary Table 1. All patients received intravenous antibiotic prophylaxis (cefazolin 2 g) at induction, repeated in case of duration of operation higher than 6 hours. Furthermore, an adjunctive antibiotic dose (metronidazole 500 mg) was administered at the time of bowel resection, when performed. All patients received low-molecular weight heparin (enoxaparin sodium 4000UI/24 hours) subcutaneously 12 hours after the operation. The decision of administering a blood transfusion was made during or after surgery according to patient hemodynamic conditions and hemoglobin levels. Postoperative recovery was calculated starting from the first postoperative day to the day of hospital discharge. Complications were prospectively specified and graded according to the Franco-Italian glossary.15 Tumor size was assessed through an integrated pre-operative clinical and instrumental examination, and definitive tumor size was established on a definitive histological specimen. The type of resection was defined based on the status of the pathologic margins: R0, microscopically negative (free margin <5 mm, it was specified in the histologic report); R1, microscopically positive; and R2, macroscopically (grossly) positive. In case of concern for the status of surgical margins, intraoperative frozen section analysis was performed and if required, and additional surgical resection was performed. In all patients, pelvic side wall involvement was confirmed at final histology. Disease-free survival was calculated from the date of primary surgery to the time of recurrence. Overall survival was defined as the time from primary surgery to death.
Supplemental material
Ontogenetic anatomy and surgical principles of laparoscopic LEER
According to Hockel’s previous publications the female pelvis could be divided into ontogenetic compartments.16–20 Briefly, the endopelvic compartment including the rectum with its mesorectum, the bladder dome and the internal uro-genital sinus (composed of urethra, distal vagina, distal rectovaginal septum); the mesopelvic compartment including the gonadal compartment (composed of the ovaries and mesovaries), the Mullerian compartment (containing the fallopian tubes, uterus, proximal vagina, proximal mesometrium and mesocolpium), ureters, bladder trigone and finally the urogenital mesentery (composed of the infundibulopelvic ligament, mesoureter, distal bladder mesentery, distal mesometrium, mesocolpium); and the ectopelvic compartment including pelvic epidermis, dermis and hypodermis, pelvic parietal peritoneum and pelvic bones and muscles; the pelvic orifice composed of the vulva except labia majora, meatus urethrae, perineum and ventral anus.
Although the LEER technique has been classically conceived within exenterative surgery, our laparoscopically modified technique included the possibility of performing a unilateral LEER with bladder and rectum sparing. Laparoscopic LEER has been defined as the laparoscopic resection of the Müllerian compartment en bloc with the gonadal compartment and with the proximal part of the pelvic urogenital mesentery and the internal iliac vascular compartment, including all parietal branches of the iliac vessel system as the ascending lumbar vein, superior gluteal artery and vein, inferior gluteal artery and vein, internal pudendal artery and vein, and internal iliac artery and vein at bifurcation. In certain cases, in order to ensure the completeness of the caudal resection, the distal parts of the urogenital mesentery, the pubo-, ilio-, and coccygeus muscles together with the mesopelvic suspensorium are included in the specimen. The complete resection of the two, bladder and/or of the hindgut compartments was performed, as previously described in the classic LEER technique, in case of vesical or rectal involvement.7 Regarding the possibility of ureteral preservation, attention has been focused on the level of the tumorous infiltration, according to the ontogenetic theory and to our previous experience on pelvic side wall disease in benign pathology.21 In particular two situations must be considered: the dorsal compartment is involved (posterior mesometrium) with infiltration of the hypogastric plexus and extension to the sacral fascia in front of the second and the third sacral routes; and the lateral compartment is involved (vascular mesometrium) with infiltration of the uterine vessels up to the level of the internal iliac branches and to the sciatic innervation with complete ureteral obstruction.
In the first scenario, the ureter is preserved, even if it is necessary to completely remove the pelvic innervation and an ‘en bloc’ resection of the sacral fascia immediately above the sacral innervation. In the second scenario, the ureter cannot be spared, for technical and oncological reasons, and it is necessary to remove both the lateral and the dorsal compartment as quite often the disease is crossing dorsally trough the hypogastric plexus. Although radiotherapy could compromise vascularization, due to the unilaterality of the resection, in the absence of previous brachytherapy, previous irradiation is not considered a contraindication to organ sparing procedures. In primary cervical cancer patients, therapeutic lymphadenectomy, as described by Hockel et al,22 is performed. In other patients, systematic or selective lymphadenectomy is performed according to tumor type and previous surgery.
Results
During the study period, a total of 39 patients underwent a LEER due to gynecological cancer infiltrating the pelvic side wall, 21 (53.8%) patients underwent a LEER with the standard open approach, while the remaining 18 (46.2%) patients were eligible for the laparoscopic approach and were included in the analysis. The general patient characteristics are shown in Table 1. Median age was 53 years (range; 32–75) and median BMI was 24 kg/m2 (range; 17–35). Laparoscopic LEER was performed as primary treatment for newly diagnosed tumors in eight patients (44.4%), and for treatment recurrent disease in the other 10 (55.6%) patients. There were no conversions to laparotomy. Only four patients (22.2%) needed intraoperative blood transfusion. In seven (38.9%) patients, post-operative admission to intensive care unit was required. Three (16.7%) intraoperative complications occurred, one vesical, one ureteral, and one vascular injury. All intraoperative complications were managed laparoscopically. Table 2 describes each patient independently, showing clinical, surgical, and oncological characteristics. Among patients undergoing laparoscopic LEER as primary treatment, one had a uterine leiomyosarcoma infiltrating the retroperitoneal tissues, for whom any other type of treatment would have been considered palliative. The other seven patients had locally advanced cervical cancer, and among them, only one underwent a laparoscopic LEER as exclusive primary treatment because she had mucinous gastric-type cervical cancer with distal parametrial involvement. The other two patients had progression of disease during neoadjuvant chemoradiotherapy and the remaining four patients had progression during neoadjuvant chemotherapy.
Distribution of patient characteristics
Details of patient characteristics
Complete resection with free margins of surgical resection was achieved at final histological evaluation in all patients. All patients underwent removal of the pelvic perivisceral fat and of the internal iliac vessels. In seven (38.9%) patients, a ureteral resection was required. Three total (16.7%) and three subtotal (16.7%) bladder resections were performed. When complete cystectomy was performed, in two (11.1%) patients the urethra was also resected. In one (5.6%) patient, total laparoscopic unilateral nephrouretherectomy was required. The rectum was removed in four (22.2%) patients. Pelvic lymphadenectomy was performed in 11 (61.1%) patients, and para-aortic lymphadenectomy in five (27.8%) patients. Removal of the obturator nerve was required in only one patient. Resection of pelvic muscles was required, internal obturator muscle was resected in four (22.2%) patients, pubococcygeus muscle in six (33.3%) patients, iliococcygeus muscle in five (27.8%) patients, and coccygeus muscle in another three (16.7%) patients. Figure 1 shows the final aspect of the pelvis after a total exenteration with bilateral laparoscopic LEER. As reconstructive urinary procedures, two (11.1%) urinary diversions according to the Bricker technique, and one (5.6%) orthotopic neobladder were performed. In three (16.7%) patients vesical reconstruction and ureteral reimplantation were performed. Figure 2 and online supplementary Figure 1 show the laparoscopic exposure after laparoscopic LEER with bladder and rectum sparing. As reconstructive bowel procedures, one (5.6%) patient underwent colorectal anastomosis, and the other three (16.7%) patients received colorectal anastomosis with temporary diverting ileostomy. Urinary diversions and colorectal anastomosis were performed through a suprapubic mini-laparotomic incision of 4–5 cm, while other types of vesical reconstructions and ureteral reimplantation were performed completely by laparoscopy.
Supplemental material
Final aspect of the pelvis after a total exenteration with bilateral laparoscopic LEER. red StAR: transected stump of the internal iliac vein.
Final aspect of the pelvis after bladder-sparing laparoscopic LEER procedure. red StAR: obturator muscle. white stars: sacral routes. yellow StAR: transected stumps of the internal iliac and the gluteal veins. white arrow: intrapelvic sciatic nerve at the entrance in the great sciatic foramen.
Postoperative complications are summarized in Table 3. In total, six (33.3%) major postoperative complications were observed: three (16.7%) patients experienced moderate hydronephrosis with normal renal function, which required temporary placement of nephrostomy; one (5.6%) patient had permanent urinary retention, likely due to the overall combination of radical hysterectomy, chemotherapy, radiotherapy and finally LEER; and in two (11.1%) patients a reoperation was required, one for post-operative hemoperitoneum and another for complete vaginal cuff dehiscence.
Post-operative complications according to Franco-Italian glossary by organ system and grade
The median postoperative length of hospital stay was 10 days (range, 4–22). Median time to adjuvant therapy was 40 days (range, 26–65). Median follow-up time was 18 months (range, 2–36). During this period 11 (61.1%) patients were alive without evidence of disease and seven (38.9%) patients have had a recurence. Among patients with recurrence, six (33.3%) died of disease and one (5.6%) was under medical therapy. Therefore, overall median disease-free survival was 13 months (range, 2–31) and overall median survival was 16 months (range, 2–36).
Discussion
Our study showed that in this small series of patients, laterally extended compartment-based surgery,5–10 17 may be safely performed through laparoscopy. It should be noted that for all patients, free surgical margins were obtained, suggesting that the laparoscopic LEER technique may potentially be considered equivalent to open surgery with a comparable radicality in terms of tumor resection. To date, only one video article has demonstrated the feasibility of LEER by laparoscopic approach in a small cohort of three patients.11 Moreover, laparoscopy enables development and dissection of structures with higher optical accuracy, improving the ability to perform surgery by preserving the function of the gastrointestinal and urinary system. Additionally, the minimally invasive approach allows a finer dissection of deep vascular structures that is one of the principal surgical criticism during LEER.
Nevertheless, the favorable toxicity profile in terms of length of hospitalization and short-term complications that have permitted a short time to adjuvant treatment should not be underestimated and could improve the final oncological outcome. In our series, no perioperative mortalities were observed and 33.3% of patients experienced major post-operative complications. Specifically, in only two cases reoperation was required and in one case, and among patients who underwent bladder-sparing surgery, permanent urinary retention syndrome was diagnosed. This low rate of urinary functional impairment may be due to the ability of laparoscopy to allow for controlateral nerve-sparing surgery in patients with deep infiltrating disease.
Thus, an accurate pre-operative evaluation is crucial in assessing the feasibility of achieving complete resection. In our experience, large tumor size or disease beyond the pelvic cavity represent the contraindication to laparoscopically-modified LEER. This article is investigating not only the possibility of using a minimal invasive approach for the LEER technique, but also the possibility of performing an “organ preserving” approach with concomitant pelvic side wall resection, with the possibility of maintaining intact bladder function and vitality, even with complete resection of the parietal, vascular, and neural support. In fact, before this study, it was unclear if after resecting the pelvic side wall compartment, in terms of vascularization and innervation, the bladder function could be maintained without major complication, nor was it clear if the technical ability to access and to remove the pelvic side wall structures with preservation of the bladder was feasible. Although this strategy could be considered in contrast with the theory of the ontogenetic resection, it has to be considered that in Hoeckel’s original theory, a “less invasive” variant, the so-called extended mesometrial resection, was considered ontogenetically appropriate when a singular mesometrial infiltration without complete pelvic side wall infiltration was present.23 We have followed this principle in women without involvement of the mesometrial structures.
There are many encouraging data on the long-term oncological outcome of the LEER procedure,5–10 17 and the introduction of the laparoscopic approach may become a future alternative therapeutic option. In fact, while considering the heterogeneity of our sample and the short follow-up, our initial data show oncological outcomes comparable to the historical series of Hockel.5 On the other hand, in a time when the oncological safety of the minimally invasive approach to gynecological tumors appears to be questioned, ultra-radical laparoscopic surgery should be proposed with caution and only in carefully selected cases.24 However, because ultra-radical surgery could be associated with a deterioration of quality of life, the LEER as primary treatment could be questioned. However, from previous reports, the presence of ostomies resulted in the main factor associated to the reduction of quality of life.25 In our series only two definitive urinary ostomies were performed, therefore, in tumors poorly responsive to chemoradiation, laparoscopically-modified LEER could be a therapeutic option also at the time of primary treatment. It appears that in the hands of an expert surgeon, trained for deep pelvic radical surgery, more than one-third of patients selected for LEER may be eligible for the laparoscopic LEER with favorable results in surgical radicality and peri-operative outcomes. The major limitations of our study are its retrospective nature, the heterogeneity of primary tumors, the small sample size, and the short follow-up: however, to the best of our knowledge, this is the largest series of patients successfully treated by laparoscopic LEER. Of course, it must be underlined that although all patients included in the present study had significant retroperitoneal invasion, it should be noted that patients previously treated with radiotherapy could have lower success rates with the laparoscopic procedure. However, it must be underlined that the LEER procedure has been mainly described and performed by Hockel’s group and that in this series only one surgeon performed the procedures, therefore larger series performed by different surgeons are required to confirm the feasibility of the results. We conclude that the laparoscopic LEER procedure is an innovative technique, and the indications to this ultra-radical procedure need to be better defined. Larger prospective studies, with a longer follow-up, are required to confirm our results in order to evaluate the oncological outcomes of patients undergoing the laparoscopic LEER procedure compared with the classical open approach.
References
Footnotes
Contributors GS: conception and design of the study; manuscript preparation; data collection; data analysis and interpretation; statistical analysis; patient recruitment. MP: manuscript preparation; data analysis and interpretation; statistical analysis. VG: manuscript preparation; data analysis, and interpretation. MCDD: manuscript preparation; data collection; patient recruitment. MF: manuscript preparation; data collection; patient recruitment. GS: conception and design of the study; data analysis and interpretation. VC: conception and design of the study; data analysis and interpretation; manuscript preparation; responsible surgeon.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Data are available upon reasonable request.