Robotic Versus Laparoscopic Radical Trachelectomy for Early-Stage Cervical Cancer: Case Report and Review of Literature

Robotic Versus Laparoscopic Radical Trachelectomy for Early-Stage Cervical Cancer: Case Report and Review of Literature

Accepted Manuscript Robotic versus laparoscopic radical trachelectomy for early stage cervical cancer: A case report and review of literature Murat Ap...

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Accepted Manuscript Robotic versus laparoscopic radical trachelectomy for early stage cervical cancer: A case report and review of literature Murat Api, M.D., PhD., Aysen Boza, M.D, Mehmet Ceyhan, M.D. PII:

S1553-4650(15)01668-4

DOI:

10.1016/j.jmig.2015.11.009

Reference:

JMIG 2725

To appear in:

The Journal of Minimally Invasive Gynecology

Received Date: 19 August 2015 Revised Date:

16 November 2015

Accepted Date: 17 November 2015

Please cite this article as: Api M, Boza A, Ceyhan M, Robotic versus laparoscopic radical trachelectomy for early stage cervical cancer: A case report and review of literature, The Journal of Minimally Invasive Gynecology (2015), doi: 10.1016/j.jmig.2015.11.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1

Robotic versus laparoscopic radical trachelectomy for early stage cervical

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cancer: A case report and review of literature

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ACCEPTED MANUSCRIPT 1

Murat Api, M.D., PhD., Aysen Boza, M.D., Mehmet Ceyhan, M.D.

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Department of Obstetrics and Gynecology (Drs. Api, Boza, Ceyhan), Zeynep Kamil

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Women and Children Diseases Training and Research Hospital, Van Ipekyolu

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Women and Children Diseases Hospital

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Corresponding-author contact information: Aysen Boza, M.D.

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Serefiye District, Maresal Fevzi Cakmak Street, post code: 65100, Merkez, Van,

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Turkey. e-mail: [email protected], phone: +90 530 923 00 46, fax number: +90 432 217 63 70

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Keywords: Radical trachelectomy; fertility; cervical cancer; robotic; laparoscopy

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No author has any potential conflict of interest, scientific writing assistance and grant

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support.

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ACCEPTED MANUSCRIPT 1

Precis

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We presented a case of laparoscopic radical trachelectomy for a woman with early

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stage cervical cancer and compared laparoscopic and robotic approaches in terms of

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the preoperative, operative and postoperative outcomes.

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ACCEPTED MANUSCRIPT Abstract

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We conducted a literature review to evaluate the minimally invasive fertility sparing

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procedures namely robotic radical trachelectomy (RRT) and laparoscopic radical

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trachelectomy (LRT) in patients with early stage cervical cancer. We searched

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Pubmed, Medline, Ovid, Google Scholar and Scopus up to July 2015 by using

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keywords and their combinations of cervical cancer; early stage; fertility sparing

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surgery;

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trachelectomy. Papers giving the details of robotic and laparoscopic RTs separately

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were included. Extracted papers and their bibliographies were reviewed according to

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the purpose of the study. Demographic, surgical and clinical parameters were

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analyzed. Our study consisted of 45 cases of RRT and 216 cases (including our case)

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of LRT. Median (range) age was 29(9) years in RRT group and 32(10) years in LRT

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group (p<.001). Histologic types and stages were significantly different between the

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groups (p<.001 for both). Median length of excised parametrial tissue was

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significantly higher in RRT group (p<.001). Hysterectomy conversion rate upon the

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results of frozen section examination was significantly higher in RRT group (37%)

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than in LRT group (6.5%) (p<.001). There was significant difference in median

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lymph node counts based on the surgical approach [RRT: 22(range:21) vs. LRT:

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32(range:14), p=.02]. Estimated blood loss and duration of hospital stay were

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significantly higher in LRT group (p <.001). Mean (range) operative time was

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308(188) minutes in RRT and 296(143) in LRT (p<.001). Pregnancy, preterm and

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term birth rates (18.5%, 7.4%, 0 in RRT and 29%, 8% and 8% in LRT group,

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respectively) were similar between the groups. Thirteen women suffered from the

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recurrence of cervical cancer in LRT group and no recurrence was seen in RRT

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group. Median (range) follow-up in RRT group was 8(7.5) months and 34(20) months

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in LRT group (p<.001). Based on the reported data, LRT seems to be comparable to

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the robotic approach in the treatment of patients with early stage cervical cancer, who

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wish to preserve fertility.

trachelectomy;

robotic

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Introduction:

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Radical hysterectomy is the standard treatment for early stage cervical cancer and can

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be performed via laparotomy, laparoscopy or robot-assisted laparoscopy. Although

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the choice of surgical approach depends on the expertise of the surgeon and available

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ACCEPTED MANUSCRIPT surgical equipment, minimal invasive surgery (MIS) has become increasingly popular

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among gynecologic oncologists. In a very recent paper, MIS (laparoscopic and

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robotic) and open surgery were compared for early stage cervical cancer and it was

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found that MIS resulted in less blood loss and shorter hospital stay [1].

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Up to 42% of all cervical cancers are diagnosed in women under the age of 45 [2];

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hence fertility preservation has become a great goal of treatment. Radical

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trachelectomy (RT) is offered for young women with early stage cervical carcinoma,

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who desire fertility preservation as an alternative to radical hysterectomy. Since

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Dargent et al. [3] first described vaginal RT with laparoscopic pelvic

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lymphadenectomy in 1994; several operative techniques for preserving fertility have

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been developed. In 1997, Smith JR et al. [4] reported abdominal RT as a new

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approach in fertility sparing surgery. Laparoscopic radical trachelectomy (LRT) was

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first published as a case report by Lee CL et al. in 2003 [5]. Following laparoscopy,

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robotic radical trachelectomy (RRT) was identified in 2008 [6]. Although many

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papers have been published on RT, up-to-now only one study [7] has compared LRT

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versus RRT in seven cases. Plante et al. [8] recently reviewed the obstetrical and

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oncologic outcomes of vaginal, abdominal and endoscopic procedures.

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The aim of the present study was to present a case of LRT for early stage cervical

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cancer in a woman who wished to preserve childbearing capacity and to compare

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laparoscopic and robotic approaches in terms of the preoperative, operative and

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postoperative outcomes.

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Search engines of Pubmed, Medline, Ovid, Google Scholar and Scopus were

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evaluated up to July 2015 by using keywords and their combinations of cervical

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cancer; early stage; fertility sparing surgery; radical trachelectomy; robotic

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trachelectomy and laparoscopic trachelectomy. To date, 302 early stage cervical

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cancer cases managed by robotic or laparoscopic RT have been published. Papers

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giving the details of robotic and laparoscopic RTs separately were included; hence the

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recent paper [1], which revealed the results of RRT and LRT cases together, was

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excluded. Extracted papers and their bibliographies were reviewed according to the

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purpose of the study.

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Demographic (age), surgical (histologic type and stage of cervical cancer,

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ACCEPTED MANUSCRIPT preoperative conization rate, uterine artery (UA) preservation, nerve sparing rate,

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hysterectomy conversion rate upon frozen section, presence of lymphovascular space

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invasion (LVSI), tumor diameter, lymph node count, excised parametrial length) and

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clinical parameters (estimated blood loss, transfusion, duration of hospital stay,

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operative time, self-voiding day after operation, adjuvant therapy, pregnancy rate after

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RT, preterm birth rate, term birth rate, follow-up period, recurrence rate) were

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analyzed. In one paper managed by RRT, the console time (time from the beginning

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to the end of the robotic procedure) was given instead of the operative time. By

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excluding this paper [7], operative times were compared between the groups. Since

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the size of the vaginal cuff, change in hemoglobin values as well as the complication

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rates were reported in only a small number of cases, these variables were not included

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in the comparative analysis.

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All statistical analysis was performed with the Statistics Package for the Social

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Sciences version 20 (SPSS Inc. Chicago, IL). Qualitative data are expressed in

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percentage (%) and quantitative data are expressed as the median, mean and range.

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Mann Whitney U test were used for variables distributed not normally. Qualitative

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data were analyzed by using Chi square test and Fisher’s Exact test. A p value of <.05

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was accepted as statistically significant.

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Case

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A 21 year-old woman was admitted to our clinic with the complaint of post-coital

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bleeding for one year. Liquid-based cytology test revealed atypical glandular cells.

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Colposcopic examination proceeded by biopsy and endo-cervical curettage resulted in

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diagnosis of clear cell adenocarcinoma of cervix with a Ki-67 strong positivity. On

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physical examination, the cervix, vaginal fornices and parametria were all normal.

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Magnetic resonance imaging (MRI) showed tumor confined to the cervix (2.5 cm).

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LRT and lymphadenectomy were decided for this young woman with stage 1B1

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cervical cancer.

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LRT was elaborated by using four trocars; a 10-mm trocar on the umbilicus for optic

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visualization, two 5-mm on the left and right inguinal, and a 5-mm on the left para-

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umbilical locations. The uterine HOHL manipulator (Storz AG, Tuttlingen/Germany)

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was applied to the cervix for assisting adequate exposure of parametrium. The

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vesicouterine peritoneum was incised to identify vesicouterine space and it was

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ACCEPTED MANUSCRIPT extended laterally and caudally to expose vesicouterine ligament and the margin of

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upper vagina. Then, recto-vaginal spaces were dissected and widened. The round

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ligaments were spared. The proximal portion of ureter was mobilized from the

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retroperitoneum down to where it crossed under the UA. By dissecting the loose

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tissue between the ureter and UA, the ureter was separated from it. Then, the anterior

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leaf of vesicouterine ligament was dissected up to the level of the ureteral entry into

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the bladder. By dividing the vesicouterine ligament and pushing the ureter laterally,

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the ureter could be separated from the parametrium and paracolpium. Descending

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branches of the UA were coagulated and dissected, and their anterior branches were

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preserved. The lateral and posterior parametria were dissected at their origins. During

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posterior dissection,

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laparoscopically. Systematic lymphadenectomy including deep inguinal, external-

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internal iliac and obturator lymph nodes was performed. The manipulator was

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removed and the upper third of vagina was circumferentially incised 2 cm below the

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cervico-vaginal junction. A surgical glove packed with gauze was placed into the

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vagina to prevent gas leakage. Then, the circumferential incision was made to the

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cervix at the level of isthmus. The amputated cervix, vaginal fornices and bilateral

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parametria were sent for frozen section examination (Figure 1). The frozen section

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biopsy revealed no involvement of the superior margin. Utero-vaginal anastomosis

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was performed vaginally with No:0 polyglactin-910 suture on four quadrants

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separately. Estimated blood loss was 260 ml and operative time was 170 min. Patient

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was discharged from the hospital at 4th postoperative day. Histopathological result

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showed that the tumor had a diameter of 2.5x1.5x0.8 cm. The tumor was 3 cm distant

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from vaginal and 0.3 cm distant from the endometrium surgical margin. All surgical

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margins were free of tumor, no lymphovascular or parametrial involvement was noted

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and all lymph nodes (19) were negative. Urinary catheter was removed on the 7th

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postoperative day and then, the patient self-voided uneventfully. The patient was

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scheduled for three-monthly follow-up visits for two years. The cervical cytology

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repeated every 6 months have been normal during the 22-months follow-up period.

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The rest of the vaginal length was found to be 6 cm at the first visit. Her menstrual

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periods started 45 days following the operation. She has not been married nor

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planning pregnancy yet.

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Results 7

ACCEPTED MANUSCRIPT Our data consisted of 45 cases by RRT reported in 8 papers [6,7,9-14] and 216 cases

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(including our case) by LRT reported in 14 papers [5,7,15-26]. Histologic, surgical

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and clinical characteristics of RRT and LRT were shown in Table-1.

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Median (range) age was 29(9) years in RRT group and 32(10) years in LRT group

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(p<.001). Histologic types and stages were significantly different between the groups

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(p<.001 for both) (Figure 2,3). Presence of LVSI and maximum tumor size of the

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specimen were similar between the groups. Median length of the excised parametrial

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tissue was significantly higher in RRT group (p<.001). Hysterectomy conversion rate

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upon the results of frozen section was significantly higher in RRT group (37%) than

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in LRT group (6.5%) (p<.001). There was significant difference in the median lymph

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node counts based on surgical approach [RRT: 22(range:21) vs. LRT: 32(range:14),

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p=.02]. Estimated blood loss and duration of hospital stay were significantly higher in

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LRT group (p<.001). Mean (range) operative time was 308(188) minutes in RRT and

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296(143) in LRT (p<.001). Median self-voiding day was 7 in RRT and 14 in LRT

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(p=.001). In LRT group 5% of the patients and in RRT group 19% of the patients

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received adjuvant therapy (p= .01). Obstetric outcomes (pregnancy, preterm and term

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birth rate) were similar between the groups. Miscarriages were only reported in LRT

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group (16/51). Thirteen women were suffered from the recurrence of cervical cancer

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in LRT group and no recurrence was seen in RRT. Four cases died because of

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progression of cervical cancer in LRT group. Median (range) follow-up in RRT group

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was 8(7.5) months and 34(20) months in LRT group (p< .001).

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In RRT group, the complications were reported in 4 out of 27 cases (15%);

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transfusion, small bowel herniation, echymosis, neuropathy were noted in one each

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case. In LRT group, 34 out of 117 cases (29%) were suffered from various kinds of

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complications: 18 cases had transfusion, 7 cases had high residual urine in bladder, 2

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had febrile morbidity and 2 had major vessel injury. Lymphocele, vesico-vaginal

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fistula, ureteral injury, minor vessel injury and bladder hypotonia were also reported

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in one each case in LRT group. Transfusion rates were similar between the groups

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(p=.13). Additionally, some complications have not been captured yet due to the

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shorter follow up in the RRT group.

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Discussion

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Fertility sparing treatment options should always be discussed with cervical cancer

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ACCEPTED MANUSCRIPT patients in the reproductive period of their lives as a pretreatment counseling. Women

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with early stage cervical cancer are good candidates for RT. The criteria for

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appropriate candidates for vaginal RT have been first proposed in 1998 [27]: desire to

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preserve fertility, being in reproductive age, squamous carcinoma or adenocarcinoma

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histology, stage IA1 with LVSI, IA2 or IB1, lesion size ≤2cm with limited

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endocervical extension, no evidence of lymph node metastasis. Nevertheless, vaginal

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approach gives limited facility to intra-abdominal evaluation of lymph nodes.

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By comparing the laparoscopic and robotic approaches, reported papers have shown

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that there were significant differences in terms of stages and histologic types of the

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cervical cancers based on surgical approach. The rate of women with adenocarcinoma

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was 63% in RRT and 21% in LRT group. Whether histologic type is an independent

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prognostic factor in cervical cancer is debatable. Galic et al. [28] analyzed 24.562

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women with stage IB-IVB from the Surveillance, Epidemiology and End Results

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database and showed that among the women with early stage (IB1-IIA) tumors,

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patients with adenocarcinoma were more likely to die from their tumors than those

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with squamous cell carcinoma (HR=1.21; 95% CI 1.10-1.32). In our review, since

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median follow-up period was significantly different between the groups and the

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outcomes of the patients (death, loss to follow up) were not exactly reported, survival

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analysis was not applicable. In our case (adenocarcinoma), throughout 22 months of

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follow-up her cervical cytology has always been negative. As shown in Figure 3,

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stage IB1 cases were more frequent in LRT (84%) than in RRT (47%) group. Median

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maximum tumor diameter on the specimen was similar and mostly, smaller than 2 cm

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in both groups. Of patients whose tumor size > 2 cm (14 cases), 28.6% underwent

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hysterectomy. No significant difference was detected among the surgical approaches

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with regard to hysterectomy rate of the patients with tumor size > 2cm (p=.98). As a

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result, one third of the cases may lose the chance of fertility preservation if the tumor

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size >2 cm regardless of the type of the surgical procedure.

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The length of the parametrial tissue is considered to be the representative of the

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degree of radicality in cervical cancer surgery. Based on our findings, the length of

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the parametrial tissue excised on both sides was significantly wider in RRT group.

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Wider parametrial excision may be related to the larger tumor diameter in RRT group.

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Significantly higher numbers of lymph nodes were removed in LRT group compared

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to RRT group (p= .02). This difference can be explained by more sentinel lymph node

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ACCEPTED MANUSCRIPT mapping performed in RRT group. Furthermore, since the preoperative stages of RRT

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group included more IA1 cases, the lymph node removal could be rarely necessary.

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Rate of conversion from endoscopic RT to radical hysterectomy based upon frozen

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section examination was significantly higher in RRT group (p<.001). The reasons

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why RT was converted to hysterectomy were explained in RRT group by a close (<10

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mm) or involved surgical margin, positive lymph nodes [10,12] and in LRT group by

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parametrial extension of tumor, pelvic/paraaortic lymph node involvement,

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endocervical margin involvement [20, 22, 25]. Of 7 hysterectomy cases in RRT

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group; 1 was in stage IA1 and 6 were in IB1 and of 13 hysterectomy cases in LRT

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group; 3 were in stage IA2, 8 were in stage IB1, 1 was in stage IIA and the stage of

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the rest was not reported. In a case series by Nick et al. [12], significantly more

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conversion to hysterectomy was found in RRT group when compared to open RT

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(33% (4) vs. 4% (1), p=.03). They showed that the majority of the patients were stage

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IB1 and their final pathology had high-risk features (positive lymph nodes or deep

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cervical

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adenocarcinoma-in-situ. They concluded that in their series, the reason of conversion

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to hysterectomy was based on tumor biology rather than deficiency in surgical

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technique.

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Theoretically, care should be taken to preserve the main branch of UA during RT to

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optimize uterine vascularization in the case of future pregnancy. Nevertheless, UA

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preservation in RT has not been validated in clinical trials. Therefore, it is still

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debatable whether UA should be preserved or not. Most of the published studies on

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RT do not suggest UA preservation [29,30]. In a recent report by Vieira et al. [1], the

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UAs were preserved in 22 patients (2 in MIS group and 20 in the open surgery group).

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There were 6 pregnancies in the open surgery group with UA preservation vs. 10

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pregnancies in the open surgery group without preservation of UAs. In our study, in

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LRT group, UA preservation was performed more commonly than in RRT group.

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Cerclage was performed as if it was a last step of RT in both groups. Pregnancy,

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preterm and term birth rates were similar between groups, but these results might not

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reflect the virtual obstetric outcome for some reasons: shorter follow-up period in

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RRT group, lack of information on number of patients who attempted to get pregnant

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and lack of information on their fertility potential.

invasion)

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residual

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glandular

atypia

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ACCEPTED MANUSCRIPT Estimated blood loss, hospital stay and self-voiding day were significantly lower in

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RRT group. Robotic surgical system has some advantages such as less intraoperative

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bleeding since it provides easier vessel dissection and coagulation because of

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articulation; the nerves, lymphatics and vessels in the deep pelvis can be well

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distinguished with the help of 3 dimensional images and fine stitching decreases

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blood loss during the reanastomosis of the vagina and uterine corpus. The median

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length of hospital stay showed significant difference between the groups (RRT: 1.5

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vs. LRT: 9, p=<.001). In LRT group, there were two studies from the Far East

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countries, which might be called as outliers that lead to this difference: Park et al. [22]

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and Ebisawa et al. [25] reported the median length of hospital stay as 9 (range 3-28

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days) and 17.5 (range 7-47 days), respectively. Both Korea and Japan provided

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extensive health insurance coverage; hence most people were encouraged to stay at

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the hospital until complete recovery. When these 2 studies were excluded from

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analysis excluded, the median hospital stay in LRT group was found to be

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3.3(range:11.5) days that was still longer than RRT group (p<.001). The self-voiding

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day was twice greater in LRT group when compared to RRT group. Martin and

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Torrent [21] published 9 laparoscopic nerve sparing RT of which urinary function

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restored in 14 days, whereas Hong et al. [7] reported self-voiding day as 6.3 days in

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three robotic nerve sparing RT. Robotic surgery might provide fine dissections which

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result in better nerve-sparing.

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Operative time was found to be significantly higher in RRT group (308 min) when

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compared to LRT group (296 min) (p<.001). This difference may be explained by

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longer set-up time (time for placing all the trocars and docking the robot until the

24

surgeon is ready to sit in the console part to start the procedure) for robotic

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procedures. Hong et al. [7] by giving the console time compared three robotic and

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four laparoscopic RTs and concluded that operation time was similar between the

27

groups (275 min in RRT vs. 250 min in LRT). In order to compare the operative times

28

between different surgical procedures precisely, the definition of operative times

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should be consistent.

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Since the complications were neither classified according to a standardized system

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nor reported uniformly in the papers, they couldn’t be compared for statistical

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significance. Although total complication rates seemed to be higher in LRT group, it

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ACCEPTED MANUSCRIPT couldn’t infer that laparoscopic RT resulted in more complication than robotic RT.

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Limitations of our study are the limited number of cases reported, especially in the

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robotic arm and short follow up period for both groups. Therefore, obstetric and

4

oncologic outcomes are not thoroughly analyzed.

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To our knowledge, our case was the first reported laparoscopic radical trachelectomy

6

from Turkey. Laparoscopic approach has readily been available almost all around the

7

world especially in low-income countries and cheaper than robotic surgical system.

8

When hysterectomies are taken into account for comparison, a Health Technology

9

Assessment report [31] and a study [32] showed that the long-term effectiveness was

10

equal for robotic, laparoscopic or open hysterectomies; however robot-assisted

11

hysterectomy was more costly.

12

According to our results, minimally invasive surgery for early stage cervical cancer

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patients who wishes to preserve their childbearing capacity is feasible. Based on the

14

reported parameters laparoscopic radical trachelectomy seems to be comparable to the

15

robotic

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aforementioned benefits and resources.

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should

offer

operative

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Declaration of interest

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The authors have no conflict of interest or grant support.

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ACCEPTED MANUSCRIPT 1

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Table-1: Comparison of histological, surgical and clinical characteristics of robotic and laparoscopic radical trachelectomies

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p values

Age, median (range), year

29 (9)

32(10)

<.001

Histological subtypes, n (%) Squamous cell carcinoma Adenocarcinoma Adenosquamous carcinoma Adenosarcoma

9(33) 17(63) 0 1(4)

159 (77) 43 (21) 4 (2) 0

<.001

Stages, n(%) 1AI 1A2 1BI 1B2 2A Preoperative conization, n (%)

8 (20) 13 (33) 19 (47) 0 0 6(86)

0 28 (14) 169 (84) 2 (1) 2 (1) 59(61)

<.001

UA preservation

12 (27)

142(66)

<.001

Nerve sparing

3(6.7)

11(5)

.72

Propyhlactic cerclage

43(98)

73(86)

.03

Hysterectomy conversion rate upon frozen section, %

7(37)

13(6.5)

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Presence of LVSI, n (%)

6(26)

30(17.4)

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.25

19(16.5)

17(20.5)

.19

Lymph node count, median (range)

22(21)

32(14)

.02

Parametrial length, median (range), mm Right parametrium Left parametrium

35(12) 35(12)

15(10) 19(6)

<.001 <.001

Estimated blood loss, median (range), ml

62.5(85)

185(100)

<.001

Transfusion, %

1(3.7)

18(15.4)

.13

Hospital stay, median, day

1.5(4)

9(16)

<.001

Operative time, mean (range), min

308(188)

296(143)

<.001

Self-voiding day, median (range),day

7(1.7)

14(7)

.001

Adjuvant therapy, n, %

6(19)

10(5)

.01

Pregnancy after trachelectomy, %

5(18.5)

51(29)

.26

Preterm birth (<37 GW), %

2(7.4)

15(8)

1

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Max. tumor diameter, median ( range), mm

Term birth, %

0

14 (8)

.37

Follow-up, median (range), mo

8(7.5)

34(20)

<.001

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0

13 (6.4)

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Figure 1: Our laparoscopic trachelectomy specimen; the vaginal wall was severed by

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more than 2 cm from the cervix, and the cervix was amputated at the level of uterine

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isthmus. The hysterometry was passed through the cervical canal and the excised

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parametria were pulled by two sides.

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Figure 2: Histologic types of cervical cancers managed by either robotic radical

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trachelectomy (RRT) or laparoscopic radical trachelectomy (LRT) (p<.001, Chi

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square test). SCC: squamous cell carcinoma, AC: adenocarcinoma, ASC:

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adenosquamous carcinoma, AS: adenosarcoma

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Figure 3: Clinical stages of cervical cancers managed by either robotic radical

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trachelectomy (RRT) or laparoscopic radical trachelectomy (LRT) (p<.001, Chi

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square test).

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http://www.AAGL.org/jmig-23-2-JMIG-D-15-00491

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http://www.AAGL.org/jmig-23-2-JMIG-D-15-00491