Gynecologic Oncology 133 (2014) 180–185
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Neoadjuvant chemotherapy followed by robotic radical hysterectomy in locally advanced cervical cancer: A multi-institution study Enrico Vizza a, Giacomo Corrado a,⁎, Vanna Zanagnolo b, Tiziana Tomaselli b, Giuseppe Cutillo a, Emanuela Mancini a, Angelo Maggioni b a b
Department of Oncological Surgery, Gynecologic Oncologic Unit, “Regina Elena” National Cancer Institute, Rome, Italy Department of Gynecology, Cervical Cancer Center, European Institute of Oncology, Milan, Italy
H I G H L I G H T S • Minimally invasive surgery is one of the most exciting areas of development in gynecologic oncology. • Neo-adjuvant chemotherapy followed by radical surgery has become one of the alternatives to concomitant radio-chemotherapy. • The development of robotic technology has facilitated the application of minimally invasive techniques in gynecologic oncology.
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Article history: Received 17 October 2013 Accepted 23 February 2014 Available online 1 March 2014 Keywords: Robotic radical hysterectomy Minimally invasive surgery Locally advanced cervical cancer Neo-adjuvant chemotherapy
a b s t r a c t Objective. Minimally invasive surgery has been performed in locally advanced cervical cancer (LACC) without adverse effect in patient's overall prognosis and survival. The aim of this report is to evaluate the feasibility and morbidity of total robotic radical hysterectomy (TRRH) with pelvic lymphadenectomy in patients with LACC after neo-adjuvant chemotherapy (NACT). Methods. From February 2008 to April 2013 a retrospective data collection of women undergoing TRRH for cervical cancer stage FIGO IB2 to IIB, after neo-adjuvant chemotherapy, was conducted at “Regina Elena” National Cancer Institute of Rome and European Institute of Oncology of Milan. All patients deemed operable underwent TRRH with pelvic lymphadenectomy within 4 weeks from the last chemotherapy cycle. Results. Median operative time was 225 min (range, 105–387 min). The median blood loss was 150 mL (range, 30–700 mL). The median number of removed pelvic lymph nodes was 23 (range, 8–69). Sixteen patients had an optimal response (12 PCR, 4 pPR1) to chemotherapy, 33 patients had a pPR2 and 11 patient showed stable disease. Adjuvant therapy was administrated in 36 patients (60%). We experienced one intra-operative complication and 19 post-operative complications, but no conversions to laparotomy were necessary to manage these complications. Six patients received a blood transfusion. At the time of this report, with a median follow-up of 28.9 months, 50 patients (83%) are free from recurrence. Conclusion. This experience demonstrates the feasibility of TRRH pelvic lymphadenectomy after NACT in LACC with good accuracy and safety. © 2014 Elsevier Inc. All rights reserved.
Introduction At the present time, the standard treatment for women affected by locally advanced cervical cancer (LACC) is concomitant radiochemotherapy [1]. Neo-adjuvant chemotherapy (NACT) followed by radical surgery has become one of the alternative treatment options [2]. Nowadays the results of multicentric randomized trial SNAP01 and SNAP02 confirmed ⁎ Corresponding author at: Department of Surgical Oncology, Gynecologic Oncology Unit, “Regina Elena” National Cancer Institute — IFO, Via Elio Chianesi 53-00128, Rome, Italy. Fax: +39 06 52665173. E-mail address: [email protected] (G. Corrado).
http://dx.doi.org/10.1016/j.ygyno.2014.02.035 0090-8258/© 2014 Elsevier Inc. All rights reserved.
that regimen of paclitaxel, ifosfamide and cisplatin (TIP) is one of the most active neo-adjuvant chemotherapeutic regimens although with a considerable associated hematologic toxicity [3,4]. Possible advantages of neo-adjuvant chemotherapy prior to surgery include the potential for reducing tumor volume, increasing resectability and helping to control micro-metastatic disease [5–7]. Minimally invasive surgery has been performed in early stage cervical cancer without adverse effect on patient's prognosis and survival [8]. Our experience indicates that total laparoscopic radical hysterectomy can be performed not only in early stage cervical cancer but also in locally advanced cervical cancer after neo-adjuvant chemotherapy, with less blood loss and less intra-operative and postoperative short term complications [9]. The development of robotic technology has
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facilitated the application of minimally invasive techniques in gynecologic oncology [10], and also the feasibility of this procedure in locally advanced cervical cancer after neo-adjuvant chemotherapy, has been investigated [11]. The current multicenter study sought to evaluate and confirm the feasibility and morbidity of total robotic radical hysterectomy (TRRH) with pelvic lymphadenectomy in patients with locally advanced cervical cancer after NACT. Material and methods This multi-institutional study has involved patients from two oncological institutions: European Institute of Oncology of Milan and the “Regina Elena” National Cancer Institute of Rome. Study design and data collection From February 2008 to April 2013, patients with histologically confirmed locally advanced cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) stages IB2–IIB) [12] with clinical response after 3 courses of NACT were eligible for the study and underwent TRRH using the Da Vinci Si Surgical System® (Intuitive Surgical Inc®, 1266 Kifer Road, Building 101 Sunnyvale, CA). Pre-treatment evaluation included: medical history collection, physical examination, vaginal-pelvic examination, chest X-ray, pelvic magnetic resonance imaging (MRI) scans and Positron emission tomography scan (PET-CT). Cystoscopy and/or proctoscopy were performed in case of suspicious involvement of the bladder or of the rectum, respectively. Further eligibility criteria included: ECOG performance status of 2 or less, adequate bone marrow reserve (absolute granulocyte count ≥2000/mL, platelet count ≥100,000/mL); and adequate renal, hepatic, and cardiac functions. Patients that were not considered candidates for the robotic approach underwent abdominal radical hysterectomy (ARH). Previous abdominal surgery was not considered a contraindication for the TRRH. Approval to conduct the study was obtained independently from an internal review board at each participating institution. Informed consent to neoadjuvant chemotherapy, clinical evaluation and robotic surgery, was obtained from all patients in accordance with local and international legislation (declaration of Helsinki) [13]. All the patients who underwent TRRH were informed that the procedure could have been converted to laparotomy if necessary. Clinical patient characteristics including age, body mass index (BMI), clinical stage according to the FIGO classification, histopathologic subtype, and tumor grade were recorded. Intra-operative parameters including blood loss and complications were recorded as well blood transfusions were performed if Hb value was ≤ 7 g/dL. Postoperative parameters included short term (within 30 days of the procedure), and long term complications (more than 30 days after the procedure), length of hospitalization, time to recovery of normal bladder function, median follow-up duration, recurrence, disease-free survival (DFS), and overall survival (OS). Complications were defined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [14]. Moreover, status of the surgical margins, status and number of removed pelvic lymph nodes, length of dissected vagina and width of bilateral parametrium were evaluated.
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(PCR) with complete disappearance of tumor in the cervix and negative nodes, or a residual disease with b3 mm stromal invasion including in situ carcinoma (pPR1); and suboptimal response (SOR) consisted of persistent residual disease with N3 mm stromal invasion on surgical specimen (pPR2). After clinical evaluation and radiological of response, before and after NACT, all patients underwent TRRH with pelvic lymphadenectomy within 4 weeks from the last chemotherapy cycle. Women with positive nodes, parametrial involvement, cut-through or SOR or OPR but with positive nodes underwent further treatment (chemotherapy, external beam irradiation plus brachytherapy or chemo-radiation). Surgical procedure Patients were placed in the lithotomy position with the arms tucked at each side. After creation of a pneumoperitoneum to 12 mmHg with a trans-umbilical Veress needle, a 12-mm trocar was placed at 5 cm cranial to the umbilical. Three 8-mm trocars, specific for the Da Vinci robotic systems (Intuitive Surgical) were placed: one (arm 1) on the right side of the abdominal wall, medial and cranial to the right anterior upper iliac spine, and two on the left side of the abdominal wall, the first (arm 2) on the left lowest rib and the second (arm 3) medial and cranial to the left anterior upper iliac spine on the same line of the right trocar, and fastened to the robotic arms. An assistant 10-mm trocar was placed on the right side of the abdominal wall, 7–10 cm laterally, from the supra-umbilical trocar. After we obtained the Trendelenburg position (30 grade), the Da Vinci robotic column was positioned near the operating table between the patient's feet and docked. The instruments were introduced: a bipolar grasper and a PK grasper on the left robotic trocars (arms 2 and 3, respectively), and a monopolar scissor on the right robotic trocar (arm 1). A 30 grade Surgical Intuitive endoscope was used during all operations. No uterine manipulator was used in any patient, but the cervix were grasped with a tenaculum and a medical grade silicone balloon, named colpo-pneumo occluder (Cooper Surgical) were emplaced in vagina in order to preserve an adequate pneumoperitoneum during colpotomy. The first step of our technique consist in opening the retroperitoneal spaces according to the following sequence: paravescical space, pararectal lateral space (Latzko), pararectal medial space (Okabayashi), rectovaginal space and vescicovaginal space. The second step is the “en bloc” level 1 and level 2 pelvic lymphadenectomy according to Querleu and Morrow classification [17]. The robotic aortic lymphadenectomy was reserved to patients with pelvic nodes disease at intra-operative examination or bulking nodes identified at the time of surgery [18]. In case of positive aortic nodes at intra-operative examination, hysterectomy was not performed; patients were excluded from the protocol and were referred to the radiotherapist. In the third step Class C1 TRRH according to Querleu and Morrow classification [17] was performed. After a careful control of hemostasis, to minimize the risk of port site metastases, the vagina prior to removal of the ports and all the port sites are irrigated with 5% povidone–iodine solution prior to the completion of the surgery [19]. In all patients the urine catheter is removed 3 days after operation and patients are instructed to do intermittent self catheterization for voiding until the post-voiding residual is less than 100 mL.
Neo-adjuvant chemotherapy and evaluation of clinical response Results TIP (paclitaxel 175 mg/m2 + ifosphamide 5 g/m2 + cisplatin 75 mg/m2) [3] regimen was chosen as neo-adjuvant chemotherapy for squamous cervical carcinoma and TEP regimen (paclitaxel 175 mg/m2 + epirubicin 80 mg/m2 + cisplatin 75 mg/m2) [15] for cervical adenocarcinoma. Clinical objective tumor responses were evaluated according to the Response Evaluation Criteria in Solid Tumors criteria [16]. Pathological responses were defined as follows: optimal response (OPR) included complete pathologic response
Sixty patients were included in the study and underwent TRRH and pelvic lymphadenectomy after NACT (Table 1). Chemotherapy toxicity All women were evaluated for toxicity and response to chemotherapy. Ifosfamide was discontinued in three patients due to allergic
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Table 1 Clinical characteristics of the 60 women with cervical cancer underwent TRRH with pelvic lymphadenectomy after NACT. Characteristics
Patients
Median age (years) Median BMI (kg/m2) Median tumor size (mm) Previous abdominal surgery Histology Squamous Adenosquamous Adenocarcinoma Clear cell FIGO stage IB2 IIA IIB Grading G1 G2 G3
44 (19–72) 24 (16–34) 44 (21–70) 13 (21.6%) 40 (66.6%) 6 (10%) 12 (20%) 2 (3.4%) 34 (56.6%) 7 (11.7%) 19 (31.7%) 1 (1.6%) 18 (30%) 41 (68.3%)
reaction and the treatment was continued with the other 2 drugs of the regimen. In 5 cases the administration of chemotherapy were delayed for G3 hematologic toxicity. The most common non-hematologic toxicities were alopecia which was mostly grades 1–2 and grade 1 sensory neuropathy.
Perioperative parameters (Table 2) Median operative time (skin to skin) was 225 min (range, 105– 387 min). The median blood loss was 150 mL (range, 30–700 mL). The median number of removed pelvic lymph nodes was 23 (range, 8–69). Two patients with squamous cell carcinoma had positive pelvic nodes at frozen section and lymphadenectomy was extended to the para-aortic nodes up to the inferior mesenteric artery. The aortic nodes resulted negative. The median width of parametrium was 25 mm in both sides (range, 9–55 mm) and the median length of dissected vagina was 20 mm (range, 8–50 mm). The surgical lateral margins of parametria were free of disease in all cases. Our most significant intra-operative complication occurred in one patient: a bleeding from the left common iliac vein during pelvic lymphadenectomy, but it was managed with robotic-assisted minimally invasive surgical techniques and the postoperative recovery was uneventful. No conversion to laparotomy/laparoscopy was necessary. Six patients received a post operative blood transfusion. The median length of hospital stay was 4 days (range, 2–14 days), and in all patients the urine catheter was removed 3 days after surgery and patients are instructed to do intermittent self catheterization for voiding until the Table 2 Surgical outcome of the 60 patients with cervical cancer operated by TRRH with pelvic lymphadenectomy after NACT. Characteristics
TRRH
Median operative time (min) Median blood loss (mL) Median pelvic lymph nodes Median width right parametrium (mm) Median width left parametrium (mm) Median length vaginal cuff (mm) Major intraoperative complications Major early postoperative complications Major late postoperative complications Blood transfusion Conversion to laparotomy Reoperation Median hospital stay (days)
225 (105–387) 150 (30–700) 23 (8–69) 25 (9–55) 25 (9–55) 20 (8–50) 1 (1.6%) 19 (31.6%) 9 (15%) 6 (10%) 0 4 (6.6%) 4 (2–14)
post-voiding residual was less than 100 mL. The median time of resumption to normal bladder function was 10 days (range, 5–60 days). Complications (Table 3) There were 19 early post operative complications: two patients had a bleeding in the first postoperative day, one had a vaginal bleeding from a small artery in the right vaginal corner and another from the site of insertion of the trocar of the arm 3, and underwent laparoscopy to control bleeding; four patients had a ureteral fistula between 7th and 15th postoperative day subsequently treated with right ureter reimplantation by laparotomy in one case while the other three patients underwent placement of a ureteral stent that were removed 3 months later with no sequela; one patient, who underwent pelvic and aortic lymphadenectomy had lymphorrhea for 7 postoperative days; five patients had lymphedema (grade 2 according to CTCAE v4.03) of whom two were diagnosed with pelvic lymphocele (grades 2 and 3 according to CTCAE v4.03) as well, requiring in one case surgical excision; two patients had a umbilical port site hernia around 20th postoperative day; and one patient had vaginal cuff dehiscence which required a surgical suture through the vagina and two other patients had numbness (grade 2 according to CTCAE v4.03) in the legs which resolved spontaneously after ten days. Long term complications were: 4 patients (6.6%) suffered urinary incontinence (grade 2 according to CTCAE v4.03); 3 patients (5%) had constipation, while other 2 patients (3.3%) had dyspareunia. Of these 9 patients, 6 patients had undergone further radiotherapy. Pathological results and adjuvant treatment (Table 4) Sixteen patients had an optimal response (12 PCR, 4 pPR1) to chemotherapy, 33 patients had a pPR2 and 11 patients showed stable disease. The median tumor diameter, evaluated radiologically, prior to chemotherapy administration was 44 mm (range, 21–70 mm), while it was 10 mm (range, 0–42 mm) on final pathological evaluation. Adjuvant therapy was administrated in 36 patients (60%). Fourteen patients, 6 with parametrial involvement and 8 with pelvic lymph nodes metastasis, underwent adjuvant radio-chemotherapy. Sixteen patients underwent adjuvant radiotherapy for residual tumor size (≥ 2 cm) and/or lymph-vascular space invasion (LVSI). Six patients with pPR2 and high grade lesion received three additional cycles of chemotherapy. At the time of this report, with a median follow-up of 31 months (range, 9–71 months) 50 patients are free from recurrence with a 3 year-DFS and 3 year-OS of 84.8% and 89.4% respectively (Fig. 1A and B). There were no differences in 3 year DFS statistically significant
Table 3 Intraoperative and postoperative complications after NACT and TRRH with pelvic lymphadenectomy. Type of complication Intraoperative Vascular injury Postoperative short-term (≤30 days) Pelvic bleeding Ureteral fistula Lymphorrhoea Lymphedema Lymphocele Trocar hernia Vaginal cuff dehiscence Lower limbs neuropathy Postoperative long-term (N30 days) Urinary dysfunctions Bowel dysfunctions Vaginal and sexual dysfunctions
Patients (%) 1 (1.6%) 2 (3.3%) 4 (6.6%) 1 (1.6%) 5 (8.3%) 2 (3.3%) 2 (3.3%) 1 (1.6%) 2 (3.3%) 4 (6.6%) 3 (5%) 2 (3.3%)
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Table 4 Neoadjuvant chemotherapy regimens and pathological response after surgery. Characteristics Neoadjuvant chemotherapy regimens TIP TEP Platinum based Pathological response after surgery PCR pPR1 pPR2 SD
Patients (%) 39 (65%) 18 (30%) 3 (5%) 12 (20%) 4 (6.7%) 33 (55%) 11 (18.3%)
TIP: Taxol + Ifosfamide + Platinum; TEP: Taxol + Epirubicin + Platinum; PCR: pathologic complete response; pPR1: microscopic partial pathologic response; and pPR2: macroscopic partial pathologic response; SD: stable disease.
between FIGO stages IB2 and IIB (Fig. 1C). Ten patients had a recurrence of disease (Table 5), with a median DFS of 7 months (range, 4– 58 months). Four of these patients died of disease with a median OS of 15.3 months (range, 12–27 months). Discussion Although chemoradiation is the current standard of treatment of LACC, there is continued interest in the use of neoadjuvant chemotherapy followed by radical hysterectomy (RH) [20]. One of the advantages of NACT followed by RH relies on the removal of potential chemo resistant foci. Indeed there is an undoubtedly rate of persistence of residual tumor also after exclusive chemo-radiotherapy (CT/RT) varying between 35 and 63% [21]. Recent meta-analysis showed a significant survival benefit of NACT followed by radical surgery and exclusive CT/RT compared to radiation alone, confirming that both are effective treatment options [22,23]. Moreover we are waiting for the results of a large randomized study comparing NACT followed by RS versus exclusive CT/RT in stages IB2–IIB cervical cancer (EORTC n 55994). Robotic radical hysterectomy after NACT No large series are available thus far to analyze the surgical and oncological results of this approach in LACC. The effects of NACT on pelvic tissues are thought to increase the difficulties of surgical dissection, in particular of pelvic structures such as the bladder and ureters. Due to these difficulties, robotic techniques are generally not used to perform radical hysterectomy after NACT. In our study, we demonstrated the safety and feasibility of a robotic approach in this setting. Vitobello et al. [11] reported on the first experience of TRRH with pelvic lymphadenectomy for the treatment of LACC after NACT. Surgical outcomes were compared to those achieved by women undergoing robotic surgery for an early stage disease during the same time frame. Outcomes resulted comparable between groups in terms of operative time, blood loss, hospitalization and complications. No differences were found in terms of nodal yield, parametrial and vaginal cuff length. Our data is similar to the experience of Vitobello et al. [11] and confirm that TRRH is feasible and safe also in patients previously submitted to NACT for LACC. Moreover, we showed that surgical outcomes were similar to our recent study comparing TRRH and LRH for the treatment of LACC after NACT [24]. In a recent our multi institutional study [25] we showed that LRH may be an appropriate alternative to ARH for the treatment of women with locally advanced cervical cancer treated with neoadjuvant chemotherapy. Complication rates and perioperative outcomes between open and laparoscopic groups were equivalent. Although our study is hardly comparable with that of Ghezzi et al. [25], operative time and hospital stay seem to be equivalent when robotic and laparoscopic approaches are compared, while blood loss was less in TRRH compared to LRH (150 vs 265 mL). Although not clinically relevant in a normal population, it could be an important issue in patients who already have received chemotherapy and may
Fig. 1. Kaplan–Meier curves for 3 years disease-free survival (A), 3 years overall survival (B) and 3 years disease-free survival between FIGO stage IB2 and IIB with log rang test (C).
need additional adjuvant treatment. However, we observed a higher number of major early complications (31.6%), even if only 18% were grade 3 according to CTCAE v4.03. This last percentage is similar to other studies published in the literature on robotic radical hysterectomy with or without neoadjuvant chemotherapy in cervical cancer [11,26]. Moreover, we believe that this increased number of complications could be related to the learning curve since the majority of them occurred in the first few robotic procedures. Woelk JL et al. [27] in a recent study have evaluated the learning curve of robotic hysterectomy
Status (months)
AWD (29) AWD (27) AWD (24) AWD (16) DOD(12) AWD (62) DOD (27) DOD (14) DOD (16) AWD (10) Pelvic Pelvic Pelvic Pelvic bone Pelvic Pelvic Vaginal Abdominal Abdominal Vaginal
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Side of recurrence
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showing that operative time and length of stay decreased within 36 months of experience, whereas complications did not. Other studies in the treatment of early cervical cancer, comparing various types of surgical approach (robotic, laparoscopy, or laparotomy) showed equivalent/similar or lower intraoperative and postoperative complications in robot-assisted approach [28]. The type of complication differed between the laparoscopic and robotic approaches, being, vascular and bladder injury observed more frequently during conventional laparoscopic cases and nerve injury during robotic cases [29].
SD: stable disease; pPR2: macroscopic partial pathologic response; CT/RT: chemo-radiotherapy; RT: radiotherapy; CT: chemotherapy; AWD: alive with disease; and DOD: died of disease.
4 8 5 9 6 58 6 10 8 4 CT/RT RT CT/RT RT No CT/RT CT CT/RT CT CT Positive Negative Positive Negative Negative Negative Negative Positive Negative Negative SD pPR2 pPR2 pPR2 pPR2 SD pPR2 pPR2 pPR2 pPR2 C1 C1 C1 C1 C1 C1 B2 C1 B2 C1 3 3 3 3 3 3 2 2 3 3 48 43 39 50 19 36 54 41 38 44 1 2 3 4 5 6 7 8 9 10
Squamous Squamous Squamous Squamous Glassy cell Adenosquamous Adenosquamous Adenosquamous Adenosquamous Adenocarcinoma
IIB IIA IIA IIB IIB IIB IB2 IB2 IB2 IB2
Type of surgery FIGO stage Grading Histology Age Case
Table 5 Patients with recurrence of disease after NACT and TRRH with pelvic lymphadenectomy.
Pathological response
Lymph nodes status
Adjuvant therapy
Time to recurrence (months)
Oncological results Oncologic outcomes of cancer-related surgery are important for prognosis. Although our median follow-up for the RRH group is still less than 3 years, 83.3% of the patients are alive without disease that is equivalent to the other studies although the median followup is greater [25,30]. All patients underwent TRRH and pelvic lymphadenectomy successfully. Sixteen patients had an optimal response (pCR, pPR1) to chemotherapy, 33 patients had a pPR2 and 11 patients showed stable disease. Notwithstanding the combined evaluation (under anesthesia and MRI) of the cervix size, showed that 11 patients had stable disease and one of them with the invasion of the parametrium experienced a recurrence within 6 months from the operation and died of disease at 12 months. Therefore, in our recent experience, the importance of an accurate clinical evaluation after NACT is very important. The rate of adjuvant treatments was high (60%); but after neoadjuvant chemotherapy and radical surgery, six patients had parametrial involvement, eight had pelvic lymph nodes metastasis, sixteen had residual tumor size (N2 cm) and/or lymph-vascular space invasion and six had residual tumor size (N2 cm) and high grade lesion. Notwithstanding the adjuvant treatments, 25% of these patients had a recurrence of the disease. We believe that, in the future, we should understand why these patients, despite all therapies, have a poor prognosis. The assessment of lymph node status is another advantage of surgery. Lymph node status represents one of the most important risk factors in the prognosis and management of cervical carcinoma [31,32]. Metastatic pelvic node involvement ranges from 13% to 28% in early cervical cancer, while it rises up to 50% in LACC [33]. The chance of intra-operative assessment of lymph node involvement would be of utmost clinical relevance in order to select cases which may need a more radical surgical approach, with the aim to tailor the extent of radicality of both lymphadenectomy and parametrectomy [34]. Indeed the detection of tumor involvement in regular sized lymph nodes by conventional imaging is very difficult. CT scan or MR or PET fails to detect lymph node metastases in 20–50% of patients [35]. Therefore a significant number of lymph nodes harboring micro-metastases may remain unidentified and possibly undertreated [35,36]. In our study, 21.6% had one or more pelvic lymph node metastases on the final pathology report. Of these, 3 (23%) recurred within one year from the completion of adjuvant CT\RT. In conclusion, the results of a double-institutional cohort study of women receiving NACT prior to TRRH for stages IB2–IIB cervical cancer suggest that robotic surgery may allow for more minimally invasive surgery with at least comparable outcomes as non-robotic approaches, although the cost efficiency of the robotic system remains to be determined. Conflict of interest statement The authors declare to have no conflict of interest.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Neoadjuvant chemotherapy followed by robotic radical hysterectomy in locally advanced cervical cancer: A multi-institution study Enrico Vizza a, Giacomo Corrado a,⁎, Vanna Zanagnolo b, Tiziana Tomaselli b, Giuseppe Cutillo a, Emanuela Mancini a, Angelo Maggioni b a b
Department of Oncological Surgery, Gynecologic Oncologic Unit, “Regina Elena” National Cancer Institute, Rome, Italy Department of Gynecology, Cervical Cancer Center, European Institute of Oncology, Milan, Italy
H I G H L I G H T S • Minimally invasive surgery is one of the most exciting areas of development in gynecologic oncology. • Neo-adjuvant chemotherapy followed by radical surgery has become one of the alternatives to concomitant radio-chemotherapy. • The development of robotic technology has facilitated the application of minimally invasive techniques in gynecologic oncology.
a r t i c l e
i n f o
Article history: Received 17 October 2013 Accepted 23 February 2014 Available online 1 March 2014 Keywords: Robotic radical hysterectomy Minimally invasive surgery Locally advanced cervical cancer Neo-adjuvant chemotherapy
a b s t r a c t Objective. Minimally invasive surgery has been performed in locally advanced cervical cancer (LACC) without adverse effect in patient's overall prognosis and survival. The aim of this report is to evaluate the feasibility and morbidity of total robotic radical hysterectomy (TRRH) with pelvic lymphadenectomy in patients with LACC after neo-adjuvant chemotherapy (NACT). Methods. From February 2008 to April 2013 a retrospective data collection of women undergoing TRRH for cervical cancer stage FIGO IB2 to IIB, after neo-adjuvant chemotherapy, was conducted at “Regina Elena” National Cancer Institute of Rome and European Institute of Oncology of Milan. All patients deemed operable underwent TRRH with pelvic lymphadenectomy within 4 weeks from the last chemotherapy cycle. Results. Median operative time was 225 min (range, 105–387 min). The median blood loss was 150 mL (range, 30–700 mL). The median number of removed pelvic lymph nodes was 23 (range, 8–69). Sixteen patients had an optimal response (12 PCR, 4 pPR1) to chemotherapy, 33 patients had a pPR2 and 11 patient showed stable disease. Adjuvant therapy was administrated in 36 patients (60%). We experienced one intra-operative complication and 19 post-operative complications, but no conversions to laparotomy were necessary to manage these complications. Six patients received a blood transfusion. At the time of this report, with a median follow-up of 28.9 months, 50 patients (83%) are free from recurrence. Conclusion. This experience demonstrates the feasibility of TRRH pelvic lymphadenectomy after NACT in LACC with good accuracy and safety. © 2014 Elsevier Inc. All rights reserved.
Introduction At the present time, the standard treatment for women affected by locally advanced cervical cancer (LACC) is concomitant radiochemotherapy [1]. Neo-adjuvant chemotherapy (NACT) followed by radical surgery has become one of the alternative treatment options [2]. Nowadays the results of multicentric randomized trial SNAP01 and SNAP02 confirmed ⁎ Corresponding author at: Department of Surgical Oncology, Gynecologic Oncology Unit, “Regina Elena” National Cancer Institute — IFO, Via Elio Chianesi 53-00128, Rome, Italy. Fax: +39 06 52665173. E-mail address: [email protected] (G. Corrado).
http://dx.doi.org/10.1016/j.ygyno.2014.02.035 0090-8258/© 2014 Elsevier Inc. All rights reserved.
that regimen of paclitaxel, ifosfamide and cisplatin (TIP) is one of the most active neo-adjuvant chemotherapeutic regimens although with a considerable associated hematologic toxicity [3,4]. Possible advantages of neo-adjuvant chemotherapy prior to surgery include the potential for reducing tumor volume, increasing resectability and helping to control micro-metastatic disease [5–7]. Minimally invasive surgery has been performed in early stage cervical cancer without adverse effect on patient's prognosis and survival [8]. Our experience indicates that total laparoscopic radical hysterectomy can be performed not only in early stage cervical cancer but also in locally advanced cervical cancer after neo-adjuvant chemotherapy, with less blood loss and less intra-operative and postoperative short term complications [9]. The development of robotic technology has
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facilitated the application of minimally invasive techniques in gynecologic oncology [10], and also the feasibility of this procedure in locally advanced cervical cancer after neo-adjuvant chemotherapy, has been investigated [11]. The current multicenter study sought to evaluate and confirm the feasibility and morbidity of total robotic radical hysterectomy (TRRH) with pelvic lymphadenectomy in patients with locally advanced cervical cancer after NACT. Material and methods This multi-institutional study has involved patients from two oncological institutions: European Institute of Oncology of Milan and the “Regina Elena” National Cancer Institute of Rome. Study design and data collection From February 2008 to April 2013, patients with histologically confirmed locally advanced cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) stages IB2–IIB) [12] with clinical response after 3 courses of NACT were eligible for the study and underwent TRRH using the Da Vinci Si Surgical System® (Intuitive Surgical Inc®, 1266 Kifer Road, Building 101 Sunnyvale, CA). Pre-treatment evaluation included: medical history collection, physical examination, vaginal-pelvic examination, chest X-ray, pelvic magnetic resonance imaging (MRI) scans and Positron emission tomography scan (PET-CT). Cystoscopy and/or proctoscopy were performed in case of suspicious involvement of the bladder or of the rectum, respectively. Further eligibility criteria included: ECOG performance status of 2 or less, adequate bone marrow reserve (absolute granulocyte count ≥2000/mL, platelet count ≥100,000/mL); and adequate renal, hepatic, and cardiac functions. Patients that were not considered candidates for the robotic approach underwent abdominal radical hysterectomy (ARH). Previous abdominal surgery was not considered a contraindication for the TRRH. Approval to conduct the study was obtained independently from an internal review board at each participating institution. Informed consent to neoadjuvant chemotherapy, clinical evaluation and robotic surgery, was obtained from all patients in accordance with local and international legislation (declaration of Helsinki) [13]. All the patients who underwent TRRH were informed that the procedure could have been converted to laparotomy if necessary. Clinical patient characteristics including age, body mass index (BMI), clinical stage according to the FIGO classification, histopathologic subtype, and tumor grade were recorded. Intra-operative parameters including blood loss and complications were recorded as well blood transfusions were performed if Hb value was ≤ 7 g/dL. Postoperative parameters included short term (within 30 days of the procedure), and long term complications (more than 30 days after the procedure), length of hospitalization, time to recovery of normal bladder function, median follow-up duration, recurrence, disease-free survival (DFS), and overall survival (OS). Complications were defined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [14]. Moreover, status of the surgical margins, status and number of removed pelvic lymph nodes, length of dissected vagina and width of bilateral parametrium were evaluated.
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(PCR) with complete disappearance of tumor in the cervix and negative nodes, or a residual disease with b3 mm stromal invasion including in situ carcinoma (pPR1); and suboptimal response (SOR) consisted of persistent residual disease with N3 mm stromal invasion on surgical specimen (pPR2). After clinical evaluation and radiological of response, before and after NACT, all patients underwent TRRH with pelvic lymphadenectomy within 4 weeks from the last chemotherapy cycle. Women with positive nodes, parametrial involvement, cut-through or SOR or OPR but with positive nodes underwent further treatment (chemotherapy, external beam irradiation plus brachytherapy or chemo-radiation). Surgical procedure Patients were placed in the lithotomy position with the arms tucked at each side. After creation of a pneumoperitoneum to 12 mmHg with a trans-umbilical Veress needle, a 12-mm trocar was placed at 5 cm cranial to the umbilical. Three 8-mm trocars, specific for the Da Vinci robotic systems (Intuitive Surgical) were placed: one (arm 1) on the right side of the abdominal wall, medial and cranial to the right anterior upper iliac spine, and two on the left side of the abdominal wall, the first (arm 2) on the left lowest rib and the second (arm 3) medial and cranial to the left anterior upper iliac spine on the same line of the right trocar, and fastened to the robotic arms. An assistant 10-mm trocar was placed on the right side of the abdominal wall, 7–10 cm laterally, from the supra-umbilical trocar. After we obtained the Trendelenburg position (30 grade), the Da Vinci robotic column was positioned near the operating table between the patient's feet and docked. The instruments were introduced: a bipolar grasper and a PK grasper on the left robotic trocars (arms 2 and 3, respectively), and a monopolar scissor on the right robotic trocar (arm 1). A 30 grade Surgical Intuitive endoscope was used during all operations. No uterine manipulator was used in any patient, but the cervix were grasped with a tenaculum and a medical grade silicone balloon, named colpo-pneumo occluder (Cooper Surgical) were emplaced in vagina in order to preserve an adequate pneumoperitoneum during colpotomy. The first step of our technique consist in opening the retroperitoneal spaces according to the following sequence: paravescical space, pararectal lateral space (Latzko), pararectal medial space (Okabayashi), rectovaginal space and vescicovaginal space. The second step is the “en bloc” level 1 and level 2 pelvic lymphadenectomy according to Querleu and Morrow classification [17]. The robotic aortic lymphadenectomy was reserved to patients with pelvic nodes disease at intra-operative examination or bulking nodes identified at the time of surgery [18]. In case of positive aortic nodes at intra-operative examination, hysterectomy was not performed; patients were excluded from the protocol and were referred to the radiotherapist. In the third step Class C1 TRRH according to Querleu and Morrow classification [17] was performed. After a careful control of hemostasis, to minimize the risk of port site metastases, the vagina prior to removal of the ports and all the port sites are irrigated with 5% povidone–iodine solution prior to the completion of the surgery [19]. In all patients the urine catheter is removed 3 days after operation and patients are instructed to do intermittent self catheterization for voiding until the post-voiding residual is less than 100 mL.
Neo-adjuvant chemotherapy and evaluation of clinical response Results TIP (paclitaxel 175 mg/m2 + ifosphamide 5 g/m2 + cisplatin 75 mg/m2) [3] regimen was chosen as neo-adjuvant chemotherapy for squamous cervical carcinoma and TEP regimen (paclitaxel 175 mg/m2 + epirubicin 80 mg/m2 + cisplatin 75 mg/m2) [15] for cervical adenocarcinoma. Clinical objective tumor responses were evaluated according to the Response Evaluation Criteria in Solid Tumors criteria [16]. Pathological responses were defined as follows: optimal response (OPR) included complete pathologic response
Sixty patients were included in the study and underwent TRRH and pelvic lymphadenectomy after NACT (Table 1). Chemotherapy toxicity All women were evaluated for toxicity and response to chemotherapy. Ifosfamide was discontinued in three patients due to allergic
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Table 1 Clinical characteristics of the 60 women with cervical cancer underwent TRRH with pelvic lymphadenectomy after NACT. Characteristics
Patients
Median age (years) Median BMI (kg/m2) Median tumor size (mm) Previous abdominal surgery Histology Squamous Adenosquamous Adenocarcinoma Clear cell FIGO stage IB2 IIA IIB Grading G1 G2 G3
44 (19–72) 24 (16–34) 44 (21–70) 13 (21.6%) 40 (66.6%) 6 (10%) 12 (20%) 2 (3.4%) 34 (56.6%) 7 (11.7%) 19 (31.7%) 1 (1.6%) 18 (30%) 41 (68.3%)
reaction and the treatment was continued with the other 2 drugs of the regimen. In 5 cases the administration of chemotherapy were delayed for G3 hematologic toxicity. The most common non-hematologic toxicities were alopecia which was mostly grades 1–2 and grade 1 sensory neuropathy.
Perioperative parameters (Table 2) Median operative time (skin to skin) was 225 min (range, 105– 387 min). The median blood loss was 150 mL (range, 30–700 mL). The median number of removed pelvic lymph nodes was 23 (range, 8–69). Two patients with squamous cell carcinoma had positive pelvic nodes at frozen section and lymphadenectomy was extended to the para-aortic nodes up to the inferior mesenteric artery. The aortic nodes resulted negative. The median width of parametrium was 25 mm in both sides (range, 9–55 mm) and the median length of dissected vagina was 20 mm (range, 8–50 mm). The surgical lateral margins of parametria were free of disease in all cases. Our most significant intra-operative complication occurred in one patient: a bleeding from the left common iliac vein during pelvic lymphadenectomy, but it was managed with robotic-assisted minimally invasive surgical techniques and the postoperative recovery was uneventful. No conversion to laparotomy/laparoscopy was necessary. Six patients received a post operative blood transfusion. The median length of hospital stay was 4 days (range, 2–14 days), and in all patients the urine catheter was removed 3 days after surgery and patients are instructed to do intermittent self catheterization for voiding until the Table 2 Surgical outcome of the 60 patients with cervical cancer operated by TRRH with pelvic lymphadenectomy after NACT. Characteristics
TRRH
Median operative time (min) Median blood loss (mL) Median pelvic lymph nodes Median width right parametrium (mm) Median width left parametrium (mm) Median length vaginal cuff (mm) Major intraoperative complications Major early postoperative complications Major late postoperative complications Blood transfusion Conversion to laparotomy Reoperation Median hospital stay (days)
225 (105–387) 150 (30–700) 23 (8–69) 25 (9–55) 25 (9–55) 20 (8–50) 1 (1.6%) 19 (31.6%) 9 (15%) 6 (10%) 0 4 (6.6%) 4 (2–14)
post-voiding residual was less than 100 mL. The median time of resumption to normal bladder function was 10 days (range, 5–60 days). Complications (Table 3) There were 19 early post operative complications: two patients had a bleeding in the first postoperative day, one had a vaginal bleeding from a small artery in the right vaginal corner and another from the site of insertion of the trocar of the arm 3, and underwent laparoscopy to control bleeding; four patients had a ureteral fistula between 7th and 15th postoperative day subsequently treated with right ureter reimplantation by laparotomy in one case while the other three patients underwent placement of a ureteral stent that were removed 3 months later with no sequela; one patient, who underwent pelvic and aortic lymphadenectomy had lymphorrhea for 7 postoperative days; five patients had lymphedema (grade 2 according to CTCAE v4.03) of whom two were diagnosed with pelvic lymphocele (grades 2 and 3 according to CTCAE v4.03) as well, requiring in one case surgical excision; two patients had a umbilical port site hernia around 20th postoperative day; and one patient had vaginal cuff dehiscence which required a surgical suture through the vagina and two other patients had numbness (grade 2 according to CTCAE v4.03) in the legs which resolved spontaneously after ten days. Long term complications were: 4 patients (6.6%) suffered urinary incontinence (grade 2 according to CTCAE v4.03); 3 patients (5%) had constipation, while other 2 patients (3.3%) had dyspareunia. Of these 9 patients, 6 patients had undergone further radiotherapy. Pathological results and adjuvant treatment (Table 4) Sixteen patients had an optimal response (12 PCR, 4 pPR1) to chemotherapy, 33 patients had a pPR2 and 11 patients showed stable disease. The median tumor diameter, evaluated radiologically, prior to chemotherapy administration was 44 mm (range, 21–70 mm), while it was 10 mm (range, 0–42 mm) on final pathological evaluation. Adjuvant therapy was administrated in 36 patients (60%). Fourteen patients, 6 with parametrial involvement and 8 with pelvic lymph nodes metastasis, underwent adjuvant radio-chemotherapy. Sixteen patients underwent adjuvant radiotherapy for residual tumor size (≥ 2 cm) and/or lymph-vascular space invasion (LVSI). Six patients with pPR2 and high grade lesion received three additional cycles of chemotherapy. At the time of this report, with a median follow-up of 31 months (range, 9–71 months) 50 patients are free from recurrence with a 3 year-DFS and 3 year-OS of 84.8% and 89.4% respectively (Fig. 1A and B). There were no differences in 3 year DFS statistically significant
Table 3 Intraoperative and postoperative complications after NACT and TRRH with pelvic lymphadenectomy. Type of complication Intraoperative Vascular injury Postoperative short-term (≤30 days) Pelvic bleeding Ureteral fistula Lymphorrhoea Lymphedema Lymphocele Trocar hernia Vaginal cuff dehiscence Lower limbs neuropathy Postoperative long-term (N30 days) Urinary dysfunctions Bowel dysfunctions Vaginal and sexual dysfunctions
Patients (%) 1 (1.6%) 2 (3.3%) 4 (6.6%) 1 (1.6%) 5 (8.3%) 2 (3.3%) 2 (3.3%) 1 (1.6%) 2 (3.3%) 4 (6.6%) 3 (5%) 2 (3.3%)
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Table 4 Neoadjuvant chemotherapy regimens and pathological response after surgery. Characteristics Neoadjuvant chemotherapy regimens TIP TEP Platinum based Pathological response after surgery PCR pPR1 pPR2 SD
Patients (%) 39 (65%) 18 (30%) 3 (5%) 12 (20%) 4 (6.7%) 33 (55%) 11 (18.3%)
TIP: Taxol + Ifosfamide + Platinum; TEP: Taxol + Epirubicin + Platinum; PCR: pathologic complete response; pPR1: microscopic partial pathologic response; and pPR2: macroscopic partial pathologic response; SD: stable disease.
between FIGO stages IB2 and IIB (Fig. 1C). Ten patients had a recurrence of disease (Table 5), with a median DFS of 7 months (range, 4– 58 months). Four of these patients died of disease with a median OS of 15.3 months (range, 12–27 months). Discussion Although chemoradiation is the current standard of treatment of LACC, there is continued interest in the use of neoadjuvant chemotherapy followed by radical hysterectomy (RH) [20]. One of the advantages of NACT followed by RH relies on the removal of potential chemo resistant foci. Indeed there is an undoubtedly rate of persistence of residual tumor also after exclusive chemo-radiotherapy (CT/RT) varying between 35 and 63% [21]. Recent meta-analysis showed a significant survival benefit of NACT followed by radical surgery and exclusive CT/RT compared to radiation alone, confirming that both are effective treatment options [22,23]. Moreover we are waiting for the results of a large randomized study comparing NACT followed by RS versus exclusive CT/RT in stages IB2–IIB cervical cancer (EORTC n 55994). Robotic radical hysterectomy after NACT No large series are available thus far to analyze the surgical and oncological results of this approach in LACC. The effects of NACT on pelvic tissues are thought to increase the difficulties of surgical dissection, in particular of pelvic structures such as the bladder and ureters. Due to these difficulties, robotic techniques are generally not used to perform radical hysterectomy after NACT. In our study, we demonstrated the safety and feasibility of a robotic approach in this setting. Vitobello et al. [11] reported on the first experience of TRRH with pelvic lymphadenectomy for the treatment of LACC after NACT. Surgical outcomes were compared to those achieved by women undergoing robotic surgery for an early stage disease during the same time frame. Outcomes resulted comparable between groups in terms of operative time, blood loss, hospitalization and complications. No differences were found in terms of nodal yield, parametrial and vaginal cuff length. Our data is similar to the experience of Vitobello et al. [11] and confirm that TRRH is feasible and safe also in patients previously submitted to NACT for LACC. Moreover, we showed that surgical outcomes were similar to our recent study comparing TRRH and LRH for the treatment of LACC after NACT [24]. In a recent our multi institutional study [25] we showed that LRH may be an appropriate alternative to ARH for the treatment of women with locally advanced cervical cancer treated with neoadjuvant chemotherapy. Complication rates and perioperative outcomes between open and laparoscopic groups were equivalent. Although our study is hardly comparable with that of Ghezzi et al. [25], operative time and hospital stay seem to be equivalent when robotic and laparoscopic approaches are compared, while blood loss was less in TRRH compared to LRH (150 vs 265 mL). Although not clinically relevant in a normal population, it could be an important issue in patients who already have received chemotherapy and may
Fig. 1. Kaplan–Meier curves for 3 years disease-free survival (A), 3 years overall survival (B) and 3 years disease-free survival between FIGO stage IB2 and IIB with log rang test (C).
need additional adjuvant treatment. However, we observed a higher number of major early complications (31.6%), even if only 18% were grade 3 according to CTCAE v4.03. This last percentage is similar to other studies published in the literature on robotic radical hysterectomy with or without neoadjuvant chemotherapy in cervical cancer [11,26]. Moreover, we believe that this increased number of complications could be related to the learning curve since the majority of them occurred in the first few robotic procedures. Woelk JL et al. [27] in a recent study have evaluated the learning curve of robotic hysterectomy
Status (months)
AWD (29) AWD (27) AWD (24) AWD (16) DOD(12) AWD (62) DOD (27) DOD (14) DOD (16) AWD (10) Pelvic Pelvic Pelvic Pelvic bone Pelvic Pelvic Vaginal Abdominal Abdominal Vaginal
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Side of recurrence
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showing that operative time and length of stay decreased within 36 months of experience, whereas complications did not. Other studies in the treatment of early cervical cancer, comparing various types of surgical approach (robotic, laparoscopy, or laparotomy) showed equivalent/similar or lower intraoperative and postoperative complications in robot-assisted approach [28]. The type of complication differed between the laparoscopic and robotic approaches, being, vascular and bladder injury observed more frequently during conventional laparoscopic cases and nerve injury during robotic cases [29].
SD: stable disease; pPR2: macroscopic partial pathologic response; CT/RT: chemo-radiotherapy; RT: radiotherapy; CT: chemotherapy; AWD: alive with disease; and DOD: died of disease.
4 8 5 9 6 58 6 10 8 4 CT/RT RT CT/RT RT No CT/RT CT CT/RT CT CT Positive Negative Positive Negative Negative Negative Negative Positive Negative Negative SD pPR2 pPR2 pPR2 pPR2 SD pPR2 pPR2 pPR2 pPR2 C1 C1 C1 C1 C1 C1 B2 C1 B2 C1 3 3 3 3 3 3 2 2 3 3 48 43 39 50 19 36 54 41 38 44 1 2 3 4 5 6 7 8 9 10
Squamous Squamous Squamous Squamous Glassy cell Adenosquamous Adenosquamous Adenosquamous Adenosquamous Adenocarcinoma
IIB IIA IIA IIB IIB IIB IB2 IB2 IB2 IB2
Type of surgery FIGO stage Grading Histology Age Case
Table 5 Patients with recurrence of disease after NACT and TRRH with pelvic lymphadenectomy.
Pathological response
Lymph nodes status
Adjuvant therapy
Time to recurrence (months)
Oncological results Oncologic outcomes of cancer-related surgery are important for prognosis. Although our median follow-up for the RRH group is still less than 3 years, 83.3% of the patients are alive without disease that is equivalent to the other studies although the median followup is greater [25,30]. All patients underwent TRRH and pelvic lymphadenectomy successfully. Sixteen patients had an optimal response (pCR, pPR1) to chemotherapy, 33 patients had a pPR2 and 11 patients showed stable disease. Notwithstanding the combined evaluation (under anesthesia and MRI) of the cervix size, showed that 11 patients had stable disease and one of them with the invasion of the parametrium experienced a recurrence within 6 months from the operation and died of disease at 12 months. Therefore, in our recent experience, the importance of an accurate clinical evaluation after NACT is very important. The rate of adjuvant treatments was high (60%); but after neoadjuvant chemotherapy and radical surgery, six patients had parametrial involvement, eight had pelvic lymph nodes metastasis, sixteen had residual tumor size (N2 cm) and/or lymph-vascular space invasion and six had residual tumor size (N2 cm) and high grade lesion. Notwithstanding the adjuvant treatments, 25% of these patients had a recurrence of the disease. We believe that, in the future, we should understand why these patients, despite all therapies, have a poor prognosis. The assessment of lymph node status is another advantage of surgery. Lymph node status represents one of the most important risk factors in the prognosis and management of cervical carcinoma [31,32]. Metastatic pelvic node involvement ranges from 13% to 28% in early cervical cancer, while it rises up to 50% in LACC [33]. The chance of intra-operative assessment of lymph node involvement would be of utmost clinical relevance in order to select cases which may need a more radical surgical approach, with the aim to tailor the extent of radicality of both lymphadenectomy and parametrectomy [34]. Indeed the detection of tumor involvement in regular sized lymph nodes by conventional imaging is very difficult. CT scan or MR or PET fails to detect lymph node metastases in 20–50% of patients [35]. Therefore a significant number of lymph nodes harboring micro-metastases may remain unidentified and possibly undertreated [35,36]. In our study, 21.6% had one or more pelvic lymph node metastases on the final pathology report. Of these, 3 (23%) recurred within one year from the completion of adjuvant CT\RT. In conclusion, the results of a double-institutional cohort study of women receiving NACT prior to TRRH for stages IB2–IIB cervical cancer suggest that robotic surgery may allow for more minimally invasive surgery with at least comparable outcomes as non-robotic approaches, although the cost efficiency of the robotic system remains to be determined. Conflict of interest statement The authors declare to have no conflict of interest.
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