Gynecologic Oncology 139 (2015) 47–51
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Laparoscopic radical hysterectomy in cervical cancer as total mesometrial resection (L-TMMR): A multicentric experience V. Chiantera a,c,f, G. Vizzielli b,c,⁎, A. Lucidi a,b,c, V. Gallotta b, M. Petrillo a,b,c, F. Legge d, A. Fagotti e, J. Sehouli f, G. Scambia b,c, M.Z. Muallem f a
Division of Gynecologic Oncology, Foundation “Giovanni Paolo II”, University of Molise, Campobasso, Italy Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Campobasso, Italy d Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Miulli Hospital, Acquaviva delle Fonti, Italy e Division of Minimally Invasive Gynaecological Surgery, St. Maria Hospital, University of Perugia, Terni, Italy f Division of Gynecologic Oncology, Charitè University, Berlin, Germany b c
H I G H L I G H T S • Laparoscopic TMMR can be safely performed in selected cervical cancer patients. • Laparoscopic TMMR has a notable reduction in postoperative functional morbidity. • The oncological role of the L-TMMR needs further future investigations.
a r t i c l e
i n f o
Article history: Received 4 June 2015 Received in revised form 7 July 2015 Accepted 8 July 2015 Available online 10 July 2015 Keywords: Laparoscopy Cervical Cancer Total Mesometrial Resection (TMMR)
a b s t r a c t Objective. To analyze the feasibility of total mesometrial resection by laparoscopy (L-TMMR) in a multicentric series of early stage cervical cancer. Method. We prospectively evaluated a consecutive series of cervical cancer patients with pre-operative FIGO stages IA2–IB1 at the Catholic University in Rome and in Campobasso and the Charitè University in Berlin. All cases were assessed at pre-operative MRI scan and clinically confirmed by investigation under anesthesia, adhering strictly to the FIGO criteria. The surgical and post-surgical data were collected. Results. 104 women with cervical cancer were admitted between July 2013 and August 2014 and among them 71 patients with pre-operative FIGO stages IA2–IB1 were treated with L-TMMR. One laparotomic conversion was registered. The median operative time was 260 min (120–670 min), estimated blood loss was 100 cm3 (25–900 cm3), and the median length of hospital stay was 6 days (2–26 days). We observed 8 intraoperative complications including a vascular injury of the left internal iliac vein that caused conversion, 6 vesical injuries and 1 ureteral injury managed laparoscopically. Two vescico-vaginal fistula and one hemoperitoneum were observed as major post-operative complications (4.2%). Conclusion. L-TMMR can be safely performed in selected cervical cancer patients. Further larger prospective trials are needed to evaluate the oncological outcome of patients undergoing this surgical procedure. © 2015 Elsevier Inc. All rights reserved
1. Introduction The ontogenetic compartment theory states that malignant tumor growth is confined to permissive compartments derived from a common primordium in embryonic development [1–4]. Höckel et al. first investigated embryonic development of the female reproductive tract with respect to embryological different compartments [5–8] and were ⁎ Corresponding author at: Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Largo A. Gemelli, 1, 00168 Rome, Italy. E-mail address: [email protected] (G. Vizzielli).
http://dx.doi.org/10.1016/j.ygyno.2015.07.010 0090-8258/© 2015 Elsevier Inc. All rights reserved
able to define three different primordial tissue complexes from cranial to caudal: the paramesonephric–mesonephric–Müllerian tubercle complex, the deep urogenital sinus (UGS) vaginal plate complex and the superficial UGS-genital folds and tubercle. Support to this theory comes from the optimal local tumor control following total mesometrial resection (TMMR) without any subsequent adjuvant radiotherapy [9,10] in patients with cervical cancer. Although it has to be questioned whether the confirmation of these findings could fundamentally change the classification of radical hysterectomy and the indication for adjuvant radiotherapy in early stage of cervical cancer [11], various authors have recently described the TMMR as an attractive therapeutic option for
48
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
the management of this subset of patients [12–15]. However, although the TMMR is perfectly standardized in open surgery, its feasibility and safety by laparoscopy have never been tested in cervical cancer patients. With the aim to address this specific issue, we evaluated the feasibility, efficacy and safeness of the laparoscopic TMMR (L-TMMR) in a multiinstitutional case-series of women with early cervical cancer FIGO IA2–IB1. 2. Material and methods The study was approved by the local ethics committee. All patients with clinical pre-operative FIGO stages IA2–IB1 entered the study after giving informed consent. Staging was done clinically by investigation under anesthesia, adhering strictly to the FIGO criteria. All patients received preoperative pelvic MRI confirming the clinical FIGO stage obtained during examination. Patients with clinical tumor size greater than 4 cm, with parametrial infiltration or with evidence of bladder wall or rectal involvement were excluded from the protocol. Pathological upstaging was not considered an exclusion criteria in any case. Moreover, patients with morbidity that would pose a high risk on surgery (i.e.: ASA physical status classification system ≥ 3), and those with severe morbid obesity (body mass index ≥ 35) were excluded yet. All patients enrolled were prospectively submitted to L-TMMR according to compartmental theory proposed by Höckel et al. [5–8]. The proposed uterovaginal (Müllerian) compartment, identified by bottom-up sectional anatomy as the final differentiation product of the Müllerian structures, was described in previous published data by Höckel et al. [8]. Briefly, i) the cranial part of the compartment is located intraperitoneally, and consists of the Fallopian tubes, mesosalpinx, uterine corpus, and broad ligament, the latter corresponding to the peritoneal mesometrium; ii) the subperitoneal part of the Müllerian compartment (i.e.: the subperitoneal mesometrium) tapers off with bilateral wings made up of dorso-laterally directed supply tissue with the uterine and vaginal arteries and veins, lymphatic drainage, and a few lymph nodes (referred to as vascular mesometrium), and dorsally directed suspensory and fatty tissue fused to the anterior and lateral mesorectum continuous with the endopelvic fascia overlying the coccygeus muscles (referred to as ligamentous mesometrium). The pelvic visceroparietal compartments deduced from the embryonic development define the following pelvic parietal lymph-node basins: external iliac; paravisceral (i.e.: anterior internal iliac, supraobturator and infraobturator, presciatic); common iliac (including the superior gluteal); and presacral (i.e.: posterior internal iliac, aortic, and caval bifurcation). Intraoperatively, frozen sections of the pelvic lymph-nodes (including presciatic and presacral lymph-node fractions) were examined for metastases. If pelvic lymph-node metastases had been detected, ascending fractions of periaortic lymph nodes were also removed. Frozen section evaluation was also done within the intracompartmental (vaginal) resection margins. Formalin-fixed TMMR specimens and lymph-node bearing tissue classified for the pelvic basin from which it had been obtained were prepared for histopathological investigation according to the protocol of the Cancer Committee of the College of American Pathologists [16]. In order to avoid intra-abdominal tumor dissemination either a vaginal manchette was obtained at the beginning of the operation or the vagina was closed with a loop before the laparoscopic colpectomy [17]. Operative time was calculated either starting from the vaginal preparation or the pneumoperitoneum to the end of surgical procedure. The decision of performing 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. Perioperatively, all patients receive once-off intravenous antibiotic prophylaxis (cefuroxime 1.5 g) at induction and low molecular weight heparin (Fraxiparin 0.4 ml/24 h) subcutaneously 12 h after the operation. Patients were enrolled in a follow-up program of assessments at
3-month intervals. Complications were prospectively specified and graded according to the Franco-Italian glossary [18]. According to compartmental theory, an adjuvant platinum-based chemotherapy was proposed if almost two pelvic positive nodes were detected; on the other hand if a pathological FIGO stage was equal or higher IB2 or if the surgical margin of resection was positive an adjuvant concomitant radio-chemotherapy was planned. The presence of any risk factors (i.e.: disease close to margins of resection — R1, lymphovascular involvement or high degree of tumor differentiation) does not considered per se eligible for any adjuvant treatment. 2.1. Surgical procedures A step-by-step of the surgical technique of L-TMMR was performed as follow and was given surgical details in the supplemental figures. • The patients were placed in dorsal lithotomic position. In many cases an initial vaginal step was performed with vaginal “manchette” creation in order to encapsulate tumor lesion and reduce tumor spread during uterine manipulation, according to previous published data [17] (S 1). The dissection of vescico-vaginal and retto-vaginal septum was also performed keeping intact the peritoneum. To preserve pneumoperitoneum, a wet surgical towel is placed into the vagina. Subsequently, after pneumoperitoneum was created, a 10 mm 0-degree or 30-degree operative laparoscope at the umbilical site was introduced. Additional three 5-mm trocars were introduced in the lower abdominal area. • Exploration of pelvic and abdominal intraperitoneal structures. With the exception of the recto-sigmoid colon, all bowel organs are retracted ventrally and placed in the right upper abdomen. The abdominal retroperitoneum is opened by incising peritoneum at the psoas muscle parallel to the infundibulopelvic ligaments. • Exposition of the urogenital mesentery developing anteriorly the paravisceral space with the umbilical artery and the lamina vesicalis dissected from the pelvic wall and tractioned medially. • Systematic pelvic lymphadenectomy according to Höckel et al. [10] is performed and lymph-node is examined under frozen section intraoperatively. The parietal nodes of the anterior pelvic compartments (external, internal iliac and obturator) are removed by completely stripping the external and internal iliac artery and vein, exposing the proximal sciatic nerves and the lumbar rami of the sacral plexus and removing the paravisceral fat pads up to the sciatic spine. The obturator nerve, artery and vein, the arcus tendinous and proximal sciatic nerve are also exposed. Para-aortic lymph-node dissection is performed in case of pre-operative radiological suspicious or in any FIGO stage with pelvic positive nodes at frozen section. • The infundibulopelvic ligament is coagulated and cut. In order to obtain more space in the pelvis the uterus–ovarian ligament is cut with separation of the adnexae from the uterus. The adnexae are placed in a bag outside the pelvis and are retained later. • The peritoneum is incised again at the level of the right promontorium. The sigmoid colon is mobilized contralaterally and the hypogastric plexus is identified just caudal the aortic bifurcation. • Development of pre-sacral fossa with identification and isolation of the right hypogastric nerve adhering medially to the mesorectum. This maneuver is carried out down to the level where the pelvic splanchnic nerves join the right hypogastric nerves to form the right inferior hypogastric plexus. • The hypogastric nerve is lateralized in order to completely expose the ligamentous mesometrium. The proximal inferior hypogastric plexus is mobilized from the lateral surface of the dense subperitoneal connective tissue which encases the rectum enabling the transection of the latter without nerve damage (S 2–6). • A complete uterus anti-version is obtained with the assistant instrument positioned behind the cervix. The Douglas peritoneum is now incised and the recto-vaginal septum is developed. The same steps
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
•
•
•
• • •
•
are conducted contralaterally in order to prepare the ligamentum mesometrium that are now transected directly at the level of the anterior face of the rectum (S 7). In order to facilitate the previous step it is sometimes necessary to use a cranial traction to the rectum either with an additional subcostal trocar or with a trans-abdominal suture. The dorsal part of the operation is now concluded, proceeding ventrally the ureter is exposed and its route is completely exhibited until the cross with the uterine vessels. Incision of peritoneum at the level of the vescico-uterine septum with separation of bladder from the anterior cervix and the proximal vagina. The umbilical artery together with the superior bladder mesentery is separated from the anterior mesometrium with sharp dissection. The uterine arteries and veins are now coagulated and cut at their origins, this allow the vascular mesometrium to be flipped medially. The operation proceeds in the anterior compartment (S 8–12). The mesometrium is mobilized from its origin at the site of the already transected uterine artery and vein(s) towards the uterus beyond the superior surface of the ureter. The vescico-vaginal venous plexus together with the dense subperitoneal connective tissue above the prevesical segment of the ureter is coagulated and divided. After cutting the remaining dorsal attachments the ureter can be completely mobilized laterally.
Table 1 Patients' clinical–pathological characteristics. Characteristics
All cases Nr (%)
All Medium age Medium BMI Medium PS-ECOG Pathological FIGO stage IA2 IB1 IB2 IIA IIB Tumor histotype Squamous cell carcinoma Adenocarcinoma Other Tumor size (mm) (mean) Invasion depth No Yes Grading G1 G2 G3 Resection state R0 R0 b 5 mm R1 Lymphovascular involvement L0 L1 Median number of pelvic lymph-node (range) Patients with pelvic lymph node metastasis Yes No Median number of positive pelvic lymph-node (range) Para-aortic lymphadenectomy Yes No Median number of para-aortic lymph-node (range) Patients with para-aortic lymph node metastasis Yes No Adjuvant treatment Chemotherapy Radio-chemotherapy
71 47 (28–76) 24 (18–34) 0 (0–1) 3 (4.2) 61 (86.0) 4 (5.6) 2 (2.8) 1 (1.4) 55 (77.5) 14 (19.7) 2 (2.8) 22 (4–62) 25 (35.2) 46 (64.8) 3 (4.2) 36 (50.7) 32 (45.1) 63 (88.7) 8 (11.3) 0 42 (59.2) 29 (40.8) 30 (15–62) 12 (16.9) 59 (83.1) 10 (4–42) 17 (23.9) 54 (76.1) 10 (4–42) 0 71 (100)
Table 2 Perioperative outcomes. Variable
Nr (%)
All cases Median length of surgery (min) (range) Intra-operative median blood loss (ml) (range) Median number of blood transfusions (range) Intra-operative complicationsa Median length of hospitalization (days) (range) Major post-operative complications b
71 260 (120–670) 100 (25–900) 0 (0–2) 8 (11.2) 6 (2–26) 3 (4.2)
a b
6 vesical injuries, 1 ureteral injury and 1 vascular damage. Upper to G1 according to Franco-Italian glossary.
• The paracolpium placed immediately lateral the initial “manchette” is transected. In case the vaginal preparation was not originally done a loop is placed laparoscopically on the vagina about 2 cm under the cervical tumor. The vaginal wall is then incised avoiding the exposition of the tumor to the surgical field. • The TMMR-specimen is removed through the vagina and the vaginal stump is closed with laparascopical sutures.
Similar to the robotic approach, we do not readapt the natural sigma adhesions, representing the sole difference to the original method described for open surgery [1–4]. However, this may be easily implemented if desired. 3. Results Between July 2013 and August 2014 seventy-one patients with clinical pre-operative cervical cancer stages IA2–IB1 were submitted to L-TMMR. The clinico-pathological characteristics of the investigated series have been reported in Table 1. Median age of the patients was 47 years (28–76 years) and median body mass index (BMI) was 24 (18–34). FIGO stage pathological distribution was IB1 in 61 patients (86%), IA2 and IB2 in 3 (4.2%) and 4 (5.6%) women respectively, and IIA and IIB in 2 (2.8%) and 1 patients (1.4%), accordingly. Mean tumor size was 22 mm (range 4–62). None of the 71 tumors was broken up or fragmented during the course of L-TMMR. R0 resection was achieved in 63 women (89%), whereas 8 patients experienced margin resection less than 5 mm. The extended lymph node dissection led to a mean lymph node count of 30 (15–62) in the pelvis and 10 (4–42) in the infra-mesenteric region. Twelve patients exhibited pelvic lymph-node metastasis and no cases showed periaortic positive lymph nodes. As showed in Table 2, the median operating time was 260 min (range 120–670 min). The median estimated blood loss (EBL) was 100 (range 25–900 cm3) and only 4 patients were intra-operatively transfused. The median time of recovery was 6 days (range 2–26). Intra- and postoperative complications have been evaluated in all patients submitted to surgery (Table 3). There were 8 intraoperative complications (11%) including 1 vascular injuries of the iliac internal veins, 5 vesical perforation and 1 ureteral injury, which were all managed laparoscopically. In Table 3 Post-operative complications according to the Franco-Italian glossary by organ system and grade [18]. Complications
G1 (%)
G2 (%)
G3 (%)
Gastrointestinal Urinary Vascular Peripheral nerves Pelvic soft tissue Total (%)
3 (4.2)a 7 (9.8)b 0 4 (5.6)c 3 (4.2)d 17 (23.8)
0 2 (2.8) 1 (1.4) 0 0 3 (4.2)
0 0 0 0 0 0
a b
3 (4.2) 23 (32.0)
49
c d
3 paralytic ileus. 6 urinary retention, 1 hematuria. 4 numbness of the lower limbs. 2 pelvic abscesses and 1 vaginal cuff dehiscence.
50
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
Table 4 Synopsis of patients submitted to adjuvant therapy. N
Patients
Pathological stagea
Advice for adjuvant treatment
Type of adjuvant treatmentb
Adhering to protocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
#1 #2 #6 #14 #15 #16 #18 #21 #24 #33 #38 #40 #44 #47 #49 #50 #51 #52 #53 #54 #55 #56 #57 #59 #62 #71
IIA, G2, N0, R0, L1 IB1, G2, N1, R0, L0 IIB, G2, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L1 IIB, G2, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L1 IB1, G3, N0, R0, L1 IB2, G2, N1, R0, L1 IB1, G3, N0, R0, L0 IB2, G3, N0, R0, L0 IB1, G2, N1, R0, L1 IB1, G2, N1, R0, L1 IB1, G3, N1, R0, L1 IB1, G2, N1, R0, L1 IB1, G2, N0, R0, L0 IB1, G3, N1, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G2, N1, R0, L0 IB1, G2, N1, R0, L0 IB1, G3, N0, R0, L0 IIA, G2, N1, R0, L0 IB1, G3, N1, R0, L1
Stage IIA N1 (2 lymph-nodes) Infiltration of mesometrium R = 3 mm G3, L1 Infiltration of mesometrium R = 1 mm, G3 R = 2 mm, G3, L1 G3, L1 Stage IB2, N1 (2 lymp-nodes) G3 Stage IB2, R = 3 mm N1 (1 lymph-node) N1 (4 lymph-nodes) N1 (1 lymph-node), G3, L1 N1 (3 lymph-nodes) R = 2 mm G3, N1 (1 lymph-node) G3 G3 G3 N1 (1 lymph-node) N1 (4 lymph-nodes) G3 Stage IIA, N1 (14 lymph-nodes) G3, N1 (1 lymph-node), L1
RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT CT RT–CT RT–CT RT–CT CT RT–CT CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT
Yes No Yes No No Yes No No No Yes No Yes No Yes No Yes No No No No No No No No Yes No
a b
N: pelvic lymph nodal involvement; R: resection rate; L: lymph-vascular involvement; G: grading. RT–CT: radio-chemotherapy; CT: chemotherapy.
the early postoperative period (b 30 days), 3 (4%) major complications were observed: two women (2.8%) experienced vescico-peritoneal fistula, which required re-intervention with laparotomy; and one patient showed post-operative hemoperitoneum laparoscopically managed. Two pelvic abscesses were noted and controlled by medical hospitalization without surgical intervention, four patients showed low-moderate paresthesia solving without any intervention after few days, and 1 vaginal dehiscence was observed. No further late major complications (N 30 days) were observed. Moreover, twenty-six patients receiving an adjuvant treatment, although eighteen of them (69%) were referred to their own oncologists that decide to not adhere to our follow-up protocol submitting those women to concomitant radio-chemotherapy. However, among the eight patients (31%) that experienced an adjuvant treatment according to compartmental theory, three were treated with cisplatin-based chemotherapy and the remaining five women were submitted to concomitant adjuvant radio-chemotherapy (Table 4). Two recurrences were observed at this time with a median follow-up of 18 months. Both patients relapsed loco-regionally and were submitted to a pelvic exenteration. 4. Discussion To date, in the era of the minimal invasive surgery [19,20], only few reports have reported the feasibility of TMMR by robotic approach [13, 14]. We show here in a large prospective multicentric experience that compartment based surgery performed as total mesometrial resection (TMMR) combined with therapeutic lymphadenectomy first described by M. Höckel [5–8] can systematically be translated to laparoscopic procedure. Undeniably, despite the limited number of patients and the short follow-up, it should be noticed that only two (2.8%) early locoregional tumor recurrences were observed, thus suggesting that LTMMR technique may be safe with respect to local tumor control and may be considered at least equivalent to open surgery with a comparable radicalness. More in depth, regarding to specific surgical procedures, we stress that exposure of the tumor to the surgical field must strictly be avoided just diminishing a potential vaginal cuff recurrence. Regarding
the operating time, it should be noted that it was longer than other series of radical hysterectomy previously published according to the Querleu–Morrow classification [21]. However this can be explained, either by the deep difference between the two surgical classifications and the corresponding techniques, and the specific learning curve required to translate the compartment philosophy to the endoscopic approach. Moreover especially two steps of the TMMR are particularly demanding if performed laparoscopically: the natural complex eradication of some lymph node stations by laparoscopy (i.e. in the lumbosacral fossa) and the difficulty to obtain the right traction both on the uterus, the rectum and the mesometrium in order to complete the dorsal part of the operation. The difference with open surgery in exposure of the posterior compartment, cannot be neglected. On the other hand, the shorter operating time compared with the historical series by Höckel et al. [5–8] which was performed by open technique, supports literature data indicating that laparoscopic procedures are time-sparing compared to open technique, especially if performed by a surgical team with a deep experience in the endoscopic approach. Since this was the first laparoscopic experience of L-TMMR, we a priori excluded morbidly obese women (BMI ≥ 35 kg/m2). However, to detail if the obesity can potentially reduce the feasibility of L-TMMR, a pilot study is now ongoing at our Department. Moreover, the favorable toxicity profile in terms of length of hospitalization and short-term complications should not be underestimated. Indeed, even if a median of 6 days as hospital discharge seems to be a rather morbid outcome for a laparoscopic surgery in early cervical cancer, the difference with other literature series is mainly related to health system policy in Germany where the patients cannot benefit of an early discharge even when there would be the opportunity. Moreover, the two severe postoperative complications in the urinary tract and the sole vascular compartment damage are in line with an initial experience with this surgical procedure and suggest potential next future improvements. The relatively low grade post-operative autonomic urinary complications (9.8%) could be justified considering that L-TMMR technique spares the pelvic nerves that supply the bladder both in the sympathetic and parasympathetic. Additionally laparoscopy as well as the robotic
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
approach, allowing to finely prepare and completely remove compartment-associated tissue without injuring adjacent structures by respecting the filmy septa at the compartment borders, enables to develop and dissect structures with higher “optical” accuracy than open technique. In our previous experience [22], laparoscopic elective dissection of the bladder and rectal splanchnic pelvic nerves and consequently, development of a parasympathetic nerve-sparing technique were technically feasible. We believe that this L-TMMR technique is not inferior in terms of “nerve sparing” than our previous laparoscopic approach. Moreover compared with the conventional open technique TMMR we demonstrated a notable reduction in postoperative functional morbidity. However, it has to be acknowledged that the level of evidence supporting the oncological role of TMMR is still low. The large percentage (Table 4) of women which did not adhere to the compartmental theory and therefore received, according to the theory an adjuvant over-treatment, suggest that the introduction of the ontological surgery in the treatment of cervical cancer will probably need more support from the scientific community and further prospective randomized data. However, although the role of TMMR in cervical cancer remains to be definitively established, compelling data from retrospective and prospective series support its role in this clinical setting [11–15]. In conclusion, further larger prospective studies are needed in order to confirm our promising results and to better define the laparoscopic surgical steps and the subsequent oncological outcome of patients undergoing TMMR compared to a classical open surgical approach. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2015.07.010. References [1] A. Garcia-Bellido, P. Ripoli, G. Morata, Developmental compartmentalization on the wing disk of Drosophila, Nat. New Biol. 245 (1973) 251–253. [2] C. Dahmann, A.C. Oates, M. Brand, Boundary formation and maintenance in tissue development, Nat. Rev. 12 (2011) 43–55. [3] R.J. Heald, D.R.H. Rayan, Recurrence and survival after total mesorectal excision for rectal cancer, Lancet 327 (1986) 1479–1482. [4] P. Quirke, M.F. Dixon, P. Durdey, N.S. Williams, Local recurrence of rectal adenocarcinoma due to inadequate surgical resection, Lancet 2 (1986) 996–998. [5] M. Höckel, L.C. Horn, B. Hentschel, S. Höckel, G. Naumann, Total mesometrial resection: high resolution nerve-sparing radical hysterectomy based on developmentally defined surgical anatomy, Int. J. Gynecol. Cancer 13 (2003) 791–803. [6] M. Höckel, L.C. Horn, H. Fritsch, Association between the mesenchymal compartment of uterovaginal organogenesis and local tumour spread in state 1B–2B cervical carcinoma: a prospective study, Lancet Oncol. 6 (2005) 751–756.
51
[7] M. Höckel, Do we need a new classification for radical hysterectomy? Insights in surgical anatomy and local tumor spread from human embryology, Gynecol. Oncol. 1 (2007) 106–112. [8] M. Höckel, L.C. Horn, N. Manthey, U.D. Braumann, U. Wolf, G. Teichmann, K. Frauenschläger, N. Dornhöfer, J. Einenkel, Resection of the embryologically defined uterovaginal (Müllerian) compartment and pelvic control in patients with cervical cancer: a prospective analysis, Lancet Oncol. 10 (2009) 683–692. [9] M. Höckel, T. Kahn, J. Einenkel, N. Manthey, U.-D. Braumann, G. Hildebrandt, C. Leo, B. Hentschel, P. Vaupel, L.-C. Horn, Local spread of cervical cancer revisited: a clinical and pathological pattern analysis, Gynecol. Oncol. 117 (2010) 401–408. [10] M. Höckel, L.-C. Horn, E. Tetsch, J. Einenkel, Pattern analysis of regional spread and therapeutic lymph node dissection in cervical cancer based on ontogenetic anatomy, Gynecol. Oncol. 125 (2012) 168–174. [11] M. Höckel, Cancer permeates locally within ontogenetic compartments: clinical evidence and implications for cancer surgery, Future Oncol. 8 (2012) 29–36. [12] A.P. Manjunath, S. Girija, Embryologically based resection of cervical cancers: a new concept of surgical radicality, J. Obstet. Gynaecol. India 62 (1) (2012 Feb) 5–14. [13] R. Kimmig, Robotic surgery for cervical cancer. Endoscopic total mesometrial resection and therapeutic lymphadenectomy [Robotic surgery beim Zervixkarzinom. Endoskopische total emesometriale Resektion und therapeutische Lymphonodektomie], Gynakologe 45 (2012) 707–711. [14] R. Kimmig, A. Iannaccone, P. Buderath, B. Aktas, P. Wimberger, M. Heubner, Definition of compartment-based radical surgery in uterine cancer — part I. Therapeutic pelvic and periaortic lymphadenectomy by Michael Höckel translated to robotic surgery (rtLNE), ISRN Obstet. Gynecol. (2013) 297921, http://dx.doi.org/10.1155/2013/ 297921. [15] M. Höckel, B. Hentschel, L.C. Horn, Association between developmental steps in the organogenesis of the uterine cervix and locoregional progression of cervical cancer: a prospective clinicopathological analysis, Lancet Oncol. 15 (4) (Apr 2014) 445–456. [16] R.J. Kurman, M.B. Amin, Cancer Committee College of American Pathologists. Protocol for the examination of the specimens from patients with carcinomas of the cervix. A basis for checklists, Arch. Pathol. Lab. Med. 123 (1999) 55–61. [17] E. Gottschalk, M. Lanowska, V. Chiantera, S. Marnitz, A. Schneider, V. Brink-Spalink, K. Hasenbein, C. Koehler, Vaginal-assisted laparoscopic radical hysterectomy: rationale, technique, results, JSLS 15 (4) (Oct–Dec 2011) 451–459. [18] D. Chassagne, P. Sismondi, J.C. Horiot, G. Sinistero, P. Bey, P. Zola, A glossary for reporting complications of treatment in gynecological cancers, Radiother. Oncol. 26 (1993) 195–202. [19] M. Reza, S. Maeso, J.A. Blasco, E. Andradas, Meta-analysis of observational studies on the safety and effectiveness of robotic gynaecological surgery, Br. J. Surg. 97 (2010) 1772–1783. [20] P.J. Paley, D.S. Veljovich, C.A. Shah, E.N. Everett, A.E. Bondurant, C.W. Drescher, W.A. Peters III, Surgical outcomes in gynecologic oncology in the era of robotics: analysis of first 1000 cases, Am. J. Obstet. Gynecol. 204 (2011) e1–e9. [21] C.B. Kruijdenberg, L.C. van den Einden, J.C. Hendriks, P.L. Zusterzeel, R.L. Bekkers, Robot-assisted versus total laparoscopic radical hysterectomy in early cervical cancer, a review, Gynecol. Oncol. 120 (3) (Mar 2011) 334–339. [22] M. Possover, J. Quakernack, V. Chiantera, The LANN technique to reduce postoperative functional morbidity in laparoscopic radical pelvic surgery, J. Am. Coll. Surg. 201 (6) (Dec 2005) 913–917.
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Laparoscopic radical hysterectomy in cervical cancer as total mesometrial resection (L-TMMR): A multicentric experience V. Chiantera a,c,f, G. Vizzielli b,c,⁎, A. Lucidi a,b,c, V. Gallotta b, M. Petrillo a,b,c, F. Legge d, A. Fagotti e, J. Sehouli f, G. Scambia b,c, M.Z. Muallem f a
Division of Gynecologic Oncology, Foundation “Giovanni Paolo II”, University of Molise, Campobasso, Italy Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Campobasso, Italy d Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Miulli Hospital, Acquaviva delle Fonti, Italy e Division of Minimally Invasive Gynaecological Surgery, St. Maria Hospital, University of Perugia, Terni, Italy f Division of Gynecologic Oncology, Charitè University, Berlin, Germany b c
H I G H L I G H T S • Laparoscopic TMMR can be safely performed in selected cervical cancer patients. • Laparoscopic TMMR has a notable reduction in postoperative functional morbidity. • The oncological role of the L-TMMR needs further future investigations.
a r t i c l e
i n f o
Article history: Received 4 June 2015 Received in revised form 7 July 2015 Accepted 8 July 2015 Available online 10 July 2015 Keywords: Laparoscopy Cervical Cancer Total Mesometrial Resection (TMMR)
a b s t r a c t Objective. To analyze the feasibility of total mesometrial resection by laparoscopy (L-TMMR) in a multicentric series of early stage cervical cancer. Method. We prospectively evaluated a consecutive series of cervical cancer patients with pre-operative FIGO stages IA2–IB1 at the Catholic University in Rome and in Campobasso and the Charitè University in Berlin. All cases were assessed at pre-operative MRI scan and clinically confirmed by investigation under anesthesia, adhering strictly to the FIGO criteria. The surgical and post-surgical data were collected. Results. 104 women with cervical cancer were admitted between July 2013 and August 2014 and among them 71 patients with pre-operative FIGO stages IA2–IB1 were treated with L-TMMR. One laparotomic conversion was registered. The median operative time was 260 min (120–670 min), estimated blood loss was 100 cm3 (25–900 cm3), and the median length of hospital stay was 6 days (2–26 days). We observed 8 intraoperative complications including a vascular injury of the left internal iliac vein that caused conversion, 6 vesical injuries and 1 ureteral injury managed laparoscopically. Two vescico-vaginal fistula and one hemoperitoneum were observed as major post-operative complications (4.2%). Conclusion. L-TMMR can be safely performed in selected cervical cancer patients. Further larger prospective trials are needed to evaluate the oncological outcome of patients undergoing this surgical procedure. © 2015 Elsevier Inc. All rights reserved
1. Introduction The ontogenetic compartment theory states that malignant tumor growth is confined to permissive compartments derived from a common primordium in embryonic development [1–4]. Höckel et al. first investigated embryonic development of the female reproductive tract with respect to embryological different compartments [5–8] and were ⁎ Corresponding author at: Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Largo A. Gemelli, 1, 00168 Rome, Italy. E-mail address: [email protected] (G. Vizzielli).
http://dx.doi.org/10.1016/j.ygyno.2015.07.010 0090-8258/© 2015 Elsevier Inc. All rights reserved
able to define three different primordial tissue complexes from cranial to caudal: the paramesonephric–mesonephric–Müllerian tubercle complex, the deep urogenital sinus (UGS) vaginal plate complex and the superficial UGS-genital folds and tubercle. Support to this theory comes from the optimal local tumor control following total mesometrial resection (TMMR) without any subsequent adjuvant radiotherapy [9,10] in patients with cervical cancer. Although it has to be questioned whether the confirmation of these findings could fundamentally change the classification of radical hysterectomy and the indication for adjuvant radiotherapy in early stage of cervical cancer [11], various authors have recently described the TMMR as an attractive therapeutic option for
48
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
the management of this subset of patients [12–15]. However, although the TMMR is perfectly standardized in open surgery, its feasibility and safety by laparoscopy have never been tested in cervical cancer patients. With the aim to address this specific issue, we evaluated the feasibility, efficacy and safeness of the laparoscopic TMMR (L-TMMR) in a multiinstitutional case-series of women with early cervical cancer FIGO IA2–IB1. 2. Material and methods The study was approved by the local ethics committee. All patients with clinical pre-operative FIGO stages IA2–IB1 entered the study after giving informed consent. Staging was done clinically by investigation under anesthesia, adhering strictly to the FIGO criteria. All patients received preoperative pelvic MRI confirming the clinical FIGO stage obtained during examination. Patients with clinical tumor size greater than 4 cm, with parametrial infiltration or with evidence of bladder wall or rectal involvement were excluded from the protocol. Pathological upstaging was not considered an exclusion criteria in any case. Moreover, patients with morbidity that would pose a high risk on surgery (i.e.: ASA physical status classification system ≥ 3), and those with severe morbid obesity (body mass index ≥ 35) were excluded yet. All patients enrolled were prospectively submitted to L-TMMR according to compartmental theory proposed by Höckel et al. [5–8]. The proposed uterovaginal (Müllerian) compartment, identified by bottom-up sectional anatomy as the final differentiation product of the Müllerian structures, was described in previous published data by Höckel et al. [8]. Briefly, i) the cranial part of the compartment is located intraperitoneally, and consists of the Fallopian tubes, mesosalpinx, uterine corpus, and broad ligament, the latter corresponding to the peritoneal mesometrium; ii) the subperitoneal part of the Müllerian compartment (i.e.: the subperitoneal mesometrium) tapers off with bilateral wings made up of dorso-laterally directed supply tissue with the uterine and vaginal arteries and veins, lymphatic drainage, and a few lymph nodes (referred to as vascular mesometrium), and dorsally directed suspensory and fatty tissue fused to the anterior and lateral mesorectum continuous with the endopelvic fascia overlying the coccygeus muscles (referred to as ligamentous mesometrium). The pelvic visceroparietal compartments deduced from the embryonic development define the following pelvic parietal lymph-node basins: external iliac; paravisceral (i.e.: anterior internal iliac, supraobturator and infraobturator, presciatic); common iliac (including the superior gluteal); and presacral (i.e.: posterior internal iliac, aortic, and caval bifurcation). Intraoperatively, frozen sections of the pelvic lymph-nodes (including presciatic and presacral lymph-node fractions) were examined for metastases. If pelvic lymph-node metastases had been detected, ascending fractions of periaortic lymph nodes were also removed. Frozen section evaluation was also done within the intracompartmental (vaginal) resection margins. Formalin-fixed TMMR specimens and lymph-node bearing tissue classified for the pelvic basin from which it had been obtained were prepared for histopathological investigation according to the protocol of the Cancer Committee of the College of American Pathologists [16]. In order to avoid intra-abdominal tumor dissemination either a vaginal manchette was obtained at the beginning of the operation or the vagina was closed with a loop before the laparoscopic colpectomy [17]. Operative time was calculated either starting from the vaginal preparation or the pneumoperitoneum to the end of surgical procedure. The decision of performing 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. Perioperatively, all patients receive once-off intravenous antibiotic prophylaxis (cefuroxime 1.5 g) at induction and low molecular weight heparin (Fraxiparin 0.4 ml/24 h) subcutaneously 12 h after the operation. Patients were enrolled in a follow-up program of assessments at
3-month intervals. Complications were prospectively specified and graded according to the Franco-Italian glossary [18]. According to compartmental theory, an adjuvant platinum-based chemotherapy was proposed if almost two pelvic positive nodes were detected; on the other hand if a pathological FIGO stage was equal or higher IB2 or if the surgical margin of resection was positive an adjuvant concomitant radio-chemotherapy was planned. The presence of any risk factors (i.e.: disease close to margins of resection — R1, lymphovascular involvement or high degree of tumor differentiation) does not considered per se eligible for any adjuvant treatment. 2.1. Surgical procedures A step-by-step of the surgical technique of L-TMMR was performed as follow and was given surgical details in the supplemental figures. • The patients were placed in dorsal lithotomic position. In many cases an initial vaginal step was performed with vaginal “manchette” creation in order to encapsulate tumor lesion and reduce tumor spread during uterine manipulation, according to previous published data [17] (S 1). The dissection of vescico-vaginal and retto-vaginal septum was also performed keeping intact the peritoneum. To preserve pneumoperitoneum, a wet surgical towel is placed into the vagina. Subsequently, after pneumoperitoneum was created, a 10 mm 0-degree or 30-degree operative laparoscope at the umbilical site was introduced. Additional three 5-mm trocars were introduced in the lower abdominal area. • Exploration of pelvic and abdominal intraperitoneal structures. With the exception of the recto-sigmoid colon, all bowel organs are retracted ventrally and placed in the right upper abdomen. The abdominal retroperitoneum is opened by incising peritoneum at the psoas muscle parallel to the infundibulopelvic ligaments. • Exposition of the urogenital mesentery developing anteriorly the paravisceral space with the umbilical artery and the lamina vesicalis dissected from the pelvic wall and tractioned medially. • Systematic pelvic lymphadenectomy according to Höckel et al. [10] is performed and lymph-node is examined under frozen section intraoperatively. The parietal nodes of the anterior pelvic compartments (external, internal iliac and obturator) are removed by completely stripping the external and internal iliac artery and vein, exposing the proximal sciatic nerves and the lumbar rami of the sacral plexus and removing the paravisceral fat pads up to the sciatic spine. The obturator nerve, artery and vein, the arcus tendinous and proximal sciatic nerve are also exposed. Para-aortic lymph-node dissection is performed in case of pre-operative radiological suspicious or in any FIGO stage with pelvic positive nodes at frozen section. • The infundibulopelvic ligament is coagulated and cut. In order to obtain more space in the pelvis the uterus–ovarian ligament is cut with separation of the adnexae from the uterus. The adnexae are placed in a bag outside the pelvis and are retained later. • The peritoneum is incised again at the level of the right promontorium. The sigmoid colon is mobilized contralaterally and the hypogastric plexus is identified just caudal the aortic bifurcation. • Development of pre-sacral fossa with identification and isolation of the right hypogastric nerve adhering medially to the mesorectum. This maneuver is carried out down to the level where the pelvic splanchnic nerves join the right hypogastric nerves to form the right inferior hypogastric plexus. • The hypogastric nerve is lateralized in order to completely expose the ligamentous mesometrium. The proximal inferior hypogastric plexus is mobilized from the lateral surface of the dense subperitoneal connective tissue which encases the rectum enabling the transection of the latter without nerve damage (S 2–6). • A complete uterus anti-version is obtained with the assistant instrument positioned behind the cervix. The Douglas peritoneum is now incised and the recto-vaginal septum is developed. The same steps
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
•
•
•
• • •
•
are conducted contralaterally in order to prepare the ligamentum mesometrium that are now transected directly at the level of the anterior face of the rectum (S 7). In order to facilitate the previous step it is sometimes necessary to use a cranial traction to the rectum either with an additional subcostal trocar or with a trans-abdominal suture. The dorsal part of the operation is now concluded, proceeding ventrally the ureter is exposed and its route is completely exhibited until the cross with the uterine vessels. Incision of peritoneum at the level of the vescico-uterine septum with separation of bladder from the anterior cervix and the proximal vagina. The umbilical artery together with the superior bladder mesentery is separated from the anterior mesometrium with sharp dissection. The uterine arteries and veins are now coagulated and cut at their origins, this allow the vascular mesometrium to be flipped medially. The operation proceeds in the anterior compartment (S 8–12). The mesometrium is mobilized from its origin at the site of the already transected uterine artery and vein(s) towards the uterus beyond the superior surface of the ureter. The vescico-vaginal venous plexus together with the dense subperitoneal connective tissue above the prevesical segment of the ureter is coagulated and divided. After cutting the remaining dorsal attachments the ureter can be completely mobilized laterally.
Table 1 Patients' clinical–pathological characteristics. Characteristics
All cases Nr (%)
All Medium age Medium BMI Medium PS-ECOG Pathological FIGO stage IA2 IB1 IB2 IIA IIB Tumor histotype Squamous cell carcinoma Adenocarcinoma Other Tumor size (mm) (mean) Invasion depth No Yes Grading G1 G2 G3 Resection state R0 R0 b 5 mm R1 Lymphovascular involvement L0 L1 Median number of pelvic lymph-node (range) Patients with pelvic lymph node metastasis Yes No Median number of positive pelvic lymph-node (range) Para-aortic lymphadenectomy Yes No Median number of para-aortic lymph-node (range) Patients with para-aortic lymph node metastasis Yes No Adjuvant treatment Chemotherapy Radio-chemotherapy
71 47 (28–76) 24 (18–34) 0 (0–1) 3 (4.2) 61 (86.0) 4 (5.6) 2 (2.8) 1 (1.4) 55 (77.5) 14 (19.7) 2 (2.8) 22 (4–62) 25 (35.2) 46 (64.8) 3 (4.2) 36 (50.7) 32 (45.1) 63 (88.7) 8 (11.3) 0 42 (59.2) 29 (40.8) 30 (15–62) 12 (16.9) 59 (83.1) 10 (4–42) 17 (23.9) 54 (76.1) 10 (4–42) 0 71 (100)
Table 2 Perioperative outcomes. Variable
Nr (%)
All cases Median length of surgery (min) (range) Intra-operative median blood loss (ml) (range) Median number of blood transfusions (range) Intra-operative complicationsa Median length of hospitalization (days) (range) Major post-operative complications b
71 260 (120–670) 100 (25–900) 0 (0–2) 8 (11.2) 6 (2–26) 3 (4.2)
a b
6 vesical injuries, 1 ureteral injury and 1 vascular damage. Upper to G1 according to Franco-Italian glossary.
• The paracolpium placed immediately lateral the initial “manchette” is transected. In case the vaginal preparation was not originally done a loop is placed laparoscopically on the vagina about 2 cm under the cervical tumor. The vaginal wall is then incised avoiding the exposition of the tumor to the surgical field. • The TMMR-specimen is removed through the vagina and the vaginal stump is closed with laparascopical sutures.
Similar to the robotic approach, we do not readapt the natural sigma adhesions, representing the sole difference to the original method described for open surgery [1–4]. However, this may be easily implemented if desired. 3. Results Between July 2013 and August 2014 seventy-one patients with clinical pre-operative cervical cancer stages IA2–IB1 were submitted to L-TMMR. The clinico-pathological characteristics of the investigated series have been reported in Table 1. Median age of the patients was 47 years (28–76 years) and median body mass index (BMI) was 24 (18–34). FIGO stage pathological distribution was IB1 in 61 patients (86%), IA2 and IB2 in 3 (4.2%) and 4 (5.6%) women respectively, and IIA and IIB in 2 (2.8%) and 1 patients (1.4%), accordingly. Mean tumor size was 22 mm (range 4–62). None of the 71 tumors was broken up or fragmented during the course of L-TMMR. R0 resection was achieved in 63 women (89%), whereas 8 patients experienced margin resection less than 5 mm. The extended lymph node dissection led to a mean lymph node count of 30 (15–62) in the pelvis and 10 (4–42) in the infra-mesenteric region. Twelve patients exhibited pelvic lymph-node metastasis and no cases showed periaortic positive lymph nodes. As showed in Table 2, the median operating time was 260 min (range 120–670 min). The median estimated blood loss (EBL) was 100 (range 25–900 cm3) and only 4 patients were intra-operatively transfused. The median time of recovery was 6 days (range 2–26). Intra- and postoperative complications have been evaluated in all patients submitted to surgery (Table 3). There were 8 intraoperative complications (11%) including 1 vascular injuries of the iliac internal veins, 5 vesical perforation and 1 ureteral injury, which were all managed laparoscopically. In Table 3 Post-operative complications according to the Franco-Italian glossary by organ system and grade [18]. Complications
G1 (%)
G2 (%)
G3 (%)
Gastrointestinal Urinary Vascular Peripheral nerves Pelvic soft tissue Total (%)
3 (4.2)a 7 (9.8)b 0 4 (5.6)c 3 (4.2)d 17 (23.8)
0 2 (2.8) 1 (1.4) 0 0 3 (4.2)
0 0 0 0 0 0
a b
3 (4.2) 23 (32.0)
49
c d
3 paralytic ileus. 6 urinary retention, 1 hematuria. 4 numbness of the lower limbs. 2 pelvic abscesses and 1 vaginal cuff dehiscence.
50
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
Table 4 Synopsis of patients submitted to adjuvant therapy. N
Patients
Pathological stagea
Advice for adjuvant treatment
Type of adjuvant treatmentb
Adhering to protocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
#1 #2 #6 #14 #15 #16 #18 #21 #24 #33 #38 #40 #44 #47 #49 #50 #51 #52 #53 #54 #55 #56 #57 #59 #62 #71
IIA, G2, N0, R0, L1 IB1, G2, N1, R0, L0 IIB, G2, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L1 IIB, G2, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L1 IB1, G3, N0, R0, L1 IB2, G2, N1, R0, L1 IB1, G3, N0, R0, L0 IB2, G3, N0, R0, L0 IB1, G2, N1, R0, L1 IB1, G2, N1, R0, L1 IB1, G3, N1, R0, L1 IB1, G2, N1, R0, L1 IB1, G2, N0, R0, L0 IB1, G3, N1, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G3, N0, R0, L0 IB1, G2, N1, R0, L0 IB1, G2, N1, R0, L0 IB1, G3, N0, R0, L0 IIA, G2, N1, R0, L0 IB1, G3, N1, R0, L1
Stage IIA N1 (2 lymph-nodes) Infiltration of mesometrium R = 3 mm G3, L1 Infiltration of mesometrium R = 1 mm, G3 R = 2 mm, G3, L1 G3, L1 Stage IB2, N1 (2 lymp-nodes) G3 Stage IB2, R = 3 mm N1 (1 lymph-node) N1 (4 lymph-nodes) N1 (1 lymph-node), G3, L1 N1 (3 lymph-nodes) R = 2 mm G3, N1 (1 lymph-node) G3 G3 G3 N1 (1 lymph-node) N1 (4 lymph-nodes) G3 Stage IIA, N1 (14 lymph-nodes) G3, N1 (1 lymph-node), L1
RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT CT RT–CT RT–CT RT–CT CT RT–CT CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT RT–CT
Yes No Yes No No Yes No No No Yes No Yes No Yes No Yes No No No No No No No No Yes No
a b
N: pelvic lymph nodal involvement; R: resection rate; L: lymph-vascular involvement; G: grading. RT–CT: radio-chemotherapy; CT: chemotherapy.
the early postoperative period (b 30 days), 3 (4%) major complications were observed: two women (2.8%) experienced vescico-peritoneal fistula, which required re-intervention with laparotomy; and one patient showed post-operative hemoperitoneum laparoscopically managed. Two pelvic abscesses were noted and controlled by medical hospitalization without surgical intervention, four patients showed low-moderate paresthesia solving without any intervention after few days, and 1 vaginal dehiscence was observed. No further late major complications (N 30 days) were observed. Moreover, twenty-six patients receiving an adjuvant treatment, although eighteen of them (69%) were referred to their own oncologists that decide to not adhere to our follow-up protocol submitting those women to concomitant radio-chemotherapy. However, among the eight patients (31%) that experienced an adjuvant treatment according to compartmental theory, three were treated with cisplatin-based chemotherapy and the remaining five women were submitted to concomitant adjuvant radio-chemotherapy (Table 4). Two recurrences were observed at this time with a median follow-up of 18 months. Both patients relapsed loco-regionally and were submitted to a pelvic exenteration. 4. Discussion To date, in the era of the minimal invasive surgery [19,20], only few reports have reported the feasibility of TMMR by robotic approach [13, 14]. We show here in a large prospective multicentric experience that compartment based surgery performed as total mesometrial resection (TMMR) combined with therapeutic lymphadenectomy first described by M. Höckel [5–8] can systematically be translated to laparoscopic procedure. Undeniably, despite the limited number of patients and the short follow-up, it should be noticed that only two (2.8%) early locoregional tumor recurrences were observed, thus suggesting that LTMMR technique may be safe with respect to local tumor control and may be considered at least equivalent to open surgery with a comparable radicalness. More in depth, regarding to specific surgical procedures, we stress that exposure of the tumor to the surgical field must strictly be avoided just diminishing a potential vaginal cuff recurrence. Regarding
the operating time, it should be noted that it was longer than other series of radical hysterectomy previously published according to the Querleu–Morrow classification [21]. However this can be explained, either by the deep difference between the two surgical classifications and the corresponding techniques, and the specific learning curve required to translate the compartment philosophy to the endoscopic approach. Moreover especially two steps of the TMMR are particularly demanding if performed laparoscopically: the natural complex eradication of some lymph node stations by laparoscopy (i.e. in the lumbosacral fossa) and the difficulty to obtain the right traction both on the uterus, the rectum and the mesometrium in order to complete the dorsal part of the operation. The difference with open surgery in exposure of the posterior compartment, cannot be neglected. On the other hand, the shorter operating time compared with the historical series by Höckel et al. [5–8] which was performed by open technique, supports literature data indicating that laparoscopic procedures are time-sparing compared to open technique, especially if performed by a surgical team with a deep experience in the endoscopic approach. Since this was the first laparoscopic experience of L-TMMR, we a priori excluded morbidly obese women (BMI ≥ 35 kg/m2). However, to detail if the obesity can potentially reduce the feasibility of L-TMMR, a pilot study is now ongoing at our Department. Moreover, the favorable toxicity profile in terms of length of hospitalization and short-term complications should not be underestimated. Indeed, even if a median of 6 days as hospital discharge seems to be a rather morbid outcome for a laparoscopic surgery in early cervical cancer, the difference with other literature series is mainly related to health system policy in Germany where the patients cannot benefit of an early discharge even when there would be the opportunity. Moreover, the two severe postoperative complications in the urinary tract and the sole vascular compartment damage are in line with an initial experience with this surgical procedure and suggest potential next future improvements. The relatively low grade post-operative autonomic urinary complications (9.8%) could be justified considering that L-TMMR technique spares the pelvic nerves that supply the bladder both in the sympathetic and parasympathetic. Additionally laparoscopy as well as the robotic
V. Chiantera et al. / Gynecologic Oncology 139 (2015) 47–51
approach, allowing to finely prepare and completely remove compartment-associated tissue without injuring adjacent structures by respecting the filmy septa at the compartment borders, enables to develop and dissect structures with higher “optical” accuracy than open technique. In our previous experience [22], laparoscopic elective dissection of the bladder and rectal splanchnic pelvic nerves and consequently, development of a parasympathetic nerve-sparing technique were technically feasible. We believe that this L-TMMR technique is not inferior in terms of “nerve sparing” than our previous laparoscopic approach. Moreover compared with the conventional open technique TMMR we demonstrated a notable reduction in postoperative functional morbidity. However, it has to be acknowledged that the level of evidence supporting the oncological role of TMMR is still low. The large percentage (Table 4) of women which did not adhere to the compartmental theory and therefore received, according to the theory an adjuvant over-treatment, suggest that the introduction of the ontological surgery in the treatment of cervical cancer will probably need more support from the scientific community and further prospective randomized data. However, although the role of TMMR in cervical cancer remains to be definitively established, compelling data from retrospective and prospective series support its role in this clinical setting [11–15]. In conclusion, further larger prospective studies are needed in order to confirm our promising results and to better define the laparoscopic surgical steps and the subsequent oncological outcome of patients undergoing TMMR compared to a classical open surgical approach. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2015.07.010. References [1] A. Garcia-Bellido, P. Ripoli, G. Morata, Developmental compartmentalization on the wing disk of Drosophila, Nat. New Biol. 245 (1973) 251–253. [2] C. Dahmann, A.C. Oates, M. Brand, Boundary formation and maintenance in tissue development, Nat. Rev. 12 (2011) 43–55. [3] R.J. Heald, D.R.H. Rayan, Recurrence and survival after total mesorectal excision for rectal cancer, Lancet 327 (1986) 1479–1482. [4] P. Quirke, M.F. Dixon, P. Durdey, N.S. Williams, Local recurrence of rectal adenocarcinoma due to inadequate surgical resection, Lancet 2 (1986) 996–998. [5] M. Höckel, L.C. Horn, B. Hentschel, S. Höckel, G. Naumann, Total mesometrial resection: high resolution nerve-sparing radical hysterectomy based on developmentally defined surgical anatomy, Int. J. Gynecol. Cancer 13 (2003) 791–803. [6] M. Höckel, L.C. Horn, H. Fritsch, Association between the mesenchymal compartment of uterovaginal organogenesis and local tumour spread in state 1B–2B cervical carcinoma: a prospective study, Lancet Oncol. 6 (2005) 751–756.
51
[7] M. Höckel, Do we need a new classification for radical hysterectomy? Insights in surgical anatomy and local tumor spread from human embryology, Gynecol. Oncol. 1 (2007) 106–112. [8] M. Höckel, L.C. Horn, N. Manthey, U.D. Braumann, U. Wolf, G. Teichmann, K. Frauenschläger, N. Dornhöfer, J. Einenkel, Resection of the embryologically defined uterovaginal (Müllerian) compartment and pelvic control in patients with cervical cancer: a prospective analysis, Lancet Oncol. 10 (2009) 683–692. [9] M. Höckel, T. Kahn, J. Einenkel, N. Manthey, U.-D. Braumann, G. Hildebrandt, C. Leo, B. Hentschel, P. Vaupel, L.-C. Horn, Local spread of cervical cancer revisited: a clinical and pathological pattern analysis, Gynecol. Oncol. 117 (2010) 401–408. [10] M. Höckel, L.-C. Horn, E. Tetsch, J. Einenkel, Pattern analysis of regional spread and therapeutic lymph node dissection in cervical cancer based on ontogenetic anatomy, Gynecol. Oncol. 125 (2012) 168–174. [11] M. Höckel, Cancer permeates locally within ontogenetic compartments: clinical evidence and implications for cancer surgery, Future Oncol. 8 (2012) 29–36. [12] A.P. Manjunath, S. Girija, Embryologically based resection of cervical cancers: a new concept of surgical radicality, J. Obstet. Gynaecol. India 62 (1) (2012 Feb) 5–14. [13] R. Kimmig, Robotic surgery for cervical cancer. Endoscopic total mesometrial resection and therapeutic lymphadenectomy [Robotic surgery beim Zervixkarzinom. Endoskopische total emesometriale Resektion und therapeutische Lymphonodektomie], Gynakologe 45 (2012) 707–711. [14] R. Kimmig, A. Iannaccone, P. Buderath, B. Aktas, P. Wimberger, M. Heubner, Definition of compartment-based radical surgery in uterine cancer — part I. Therapeutic pelvic and periaortic lymphadenectomy by Michael Höckel translated to robotic surgery (rtLNE), ISRN Obstet. Gynecol. (2013) 297921, http://dx.doi.org/10.1155/2013/ 297921. [15] M. Höckel, B. Hentschel, L.C. Horn, Association between developmental steps in the organogenesis of the uterine cervix and locoregional progression of cervical cancer: a prospective clinicopathological analysis, Lancet Oncol. 15 (4) (Apr 2014) 445–456. [16] R.J. Kurman, M.B. Amin, Cancer Committee College of American Pathologists. Protocol for the examination of the specimens from patients with carcinomas of the cervix. A basis for checklists, Arch. Pathol. Lab. Med. 123 (1999) 55–61. [17] E. Gottschalk, M. Lanowska, V. Chiantera, S. Marnitz, A. Schneider, V. Brink-Spalink, K. Hasenbein, C. Koehler, Vaginal-assisted laparoscopic radical hysterectomy: rationale, technique, results, JSLS 15 (4) (Oct–Dec 2011) 451–459. [18] D. Chassagne, P. Sismondi, J.C. Horiot, G. Sinistero, P. Bey, P. Zola, A glossary for reporting complications of treatment in gynecological cancers, Radiother. Oncol. 26 (1993) 195–202. [19] M. Reza, S. Maeso, J.A. Blasco, E. Andradas, Meta-analysis of observational studies on the safety and effectiveness of robotic gynaecological surgery, Br. J. Surg. 97 (2010) 1772–1783. [20] P.J. Paley, D.S. Veljovich, C.A. Shah, E.N. Everett, A.E. Bondurant, C.W. Drescher, W.A. Peters III, Surgical outcomes in gynecologic oncology in the era of robotics: analysis of first 1000 cases, Am. J. Obstet. Gynecol. 204 (2011) e1–e9. [21] C.B. Kruijdenberg, L.C. van den Einden, J.C. Hendriks, P.L. Zusterzeel, R.L. Bekkers, Robot-assisted versus total laparoscopic radical hysterectomy in early cervical cancer, a review, Gynecol. Oncol. 120 (3) (Mar 2011) 334–339. [22] M. Possover, J. Quakernack, V. Chiantera, The LANN technique to reduce postoperative functional morbidity in laparoscopic radical pelvic surgery, J. Am. Coll. Surg. 201 (6) (Dec 2005) 913–917.
