- Email: [email protected]
Which role for pre-treatment laparoscopic staging?
Gynecologic Oncology 107 (2007) S101 – S105 www.elsevier.com/locate/ygyno
Which role for pre-treatment laparoscopic staging? Anna Fagotti a , Francesco Fanfani a , Romina Longo a , Francesco Legge a , Alessandra Mari a , Maria L. Gagliardi a , Giovanni Scambia a,b,⁎ a
Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Campobasso, Italy b Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy Received 6 July 2007 Available online 28 August 2007
Abstract Objective. To investigate in cervical cancer patients the impact of pre-treatment laparoscopic staging on treatment plan and disease free survival. Methods. A review of the present literature has been performed and data have been compared to results obtained in a large series of patients not surgically staged. Results. Among 134 abstracts resulting from Medline research, 13 were deemed potentially relevant to the study questions. The presence of intraperitoneal diffusion of disease can be recognized in locally advanced cervical cancer patients (LACC) in a percentage ranging between 1.9% and 29%. The rate of aortic positive nodes in clinically negative LACC patients cases has been reported between 11% and 25%, by laparoscopy. In our Division, 152 LACC patients have been treated between October 1997 and February 2007. None of the patients has been submitted to pretreatment laparoscopic staging, whereas in all cases a pre-operative MRI has been performed. With a median follow-up 28.0 months (range 3– 126 months), 31 recurrences have been observed. The 5-year DFS has been 83% and OS 90%. Although only a retrospective analysis can be carried out, such result well compares to cases surgically staged. Conclusions. Pre-treatment surgical staging can identify positive nodes in LACC patients considered clinically negative, and recognize intraperitoneal disease, thus making the physician tailor the treatment on the bases of histopathological result. Moreover, it offers the potential advantage of debulking of macroscopically positive nodes, and to transpose the ovary outside the radiation. However, the positive impact on DFS has still to be demonstrated. © 2007 Elsevier Inc. All rights reserved. Keywords: Laparoscopy; Cervical cancer; Staging
Introduction Treatment of cervical cancer greatly varies according to the stage of the disease, consisting in immediate radical surgery, exclusive chemoradiation or neoadjuvant treatment followed by radical surgery. However, despite the impact of the stage of disease on the treatment plan, cervical cancer staging is based on clinical rather than surgical assessment. This means that the extent of the disease is evaluated by the physical examination
⁎ Corresponding author. Gynecologic Oncology Unit, Catholic University, L.go A. Gemelli, 8 00168, Rome, Italy. Fax: +39 0635508736. E-mail address: [email protected] (G. Scambia). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.07.005
under anesthesia and a few other tests that are done in some cases, such as cystoscopy and proctoscopy. Among possible sites of diffusion, lymphnodal status or tumor spread within the abdominal cavity and the peritoneal surface are certainly the most difficult variables to evaluate by clinical examination with respect to a possible infiltration of the parametrium, vagina, the vesico-vaginal or recto-vaginal septum. Moreover, detection of metastatic paraaortic nodes or peritoneal carcinosis may lead to a change in the treatment plan. Although not recognized by FIGO, computed tomography (CT) and magnetic resonance imaging (MRI) are widely used for therapeutic decisions in patients with cervical cancer, with a large discrepancy between FIGO recommendations and the actual test used for cervical cancer staging [1]. However,
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correlation of CT and MRI findings with histopathological evaluation of surgical specimen is variable [2]. Surgical staging is the ideal method to determine the extent of the disease outside the cervix, vagina and parametria. The advantages of surgical exploration can be: detection of intrabdominal disease, assessment of pathological status of lymph nodes and vesico-vaginal or recto-vaginal septum and debulking of tumor involved nodes [3]. Recently, it has been shown that pre-treatment laparoscopic staging does not increase morbidity, and it has the additional advantage of less postoperative adhesion formations respect to laparotomy [4,5]. Paraaortic and pelvic lymphadenectomy can be done safely laparoscopically and can be considered as complete as by open surgery [6], and tumor invasion into the vesicocervical ligament, the rectovaginal septum or intraperitoneally can be also detected [7]. The aim of this study was to investigate in cervical cancer patients the impact of pre-treatment laparoscopic staging on treatment plan and disease free survival. To this purpose, a review of the present literature has been performed and data have been compared to results obtained in a large series of patients not surgically staged. Materials and methods A systematic review of the literature on pre-treatment laparoscopic surgical staging in cervical cancer patients has been performed until April 2003. Filters and limitations have been used to eliminate inappropriate publications. General inclusion criteria have been applied to maximize the applicability of the search results. The search strategy has combined the concepts of cervical cancer and staging laparoscopy. After filtering irrelevant publication, individual review of the abstracts has been performed to identify articles for full review. Inclusion criteria have been used for accepting studies, as follows: (1) English or French language articles reporting primary data and published in a peer review journal (not abstracts); (2) studies that include a consistent number of patients with cervical cancer undergoing staging laparoscopy. A second level of inclusion criteria has been applied to all articles identified for full text review based on a review of the abstracts. Prior to full text review, these articles have been screened to ensure that they answer the study question: impact on treatment plan and survival. Data on patient population characteristics, laparoscopic technique for staging, complications, treatment plan and follow-up have been abstracted. In addition to the above criteria used to describe an ideal study design, additional criteria for determining the quality of a given study have been developed and applied during data abstraction. These criteria have been as follows: (1) the study had a representative sample, (2) the setting and selection of the population under investigation were clearly described, (3) the study design minimized differences between patients who received the tests and (4) histopathological or clinical confirmation of disease were mentioned. Each article was reviewed by at least two reviewers. Discrepancies between reviewers were resolved by consensus. Our study population consists of 152 consecutive patients with histologically proven locally advanced cervical cancer (LACC) accrued between October 1997 and February 2007 at the Divisions of Gynecologic Oncology of the Catholic University of Rome and Campobasso. Pre-treatment work up included a medical history, clinical examination under anesthesia, chest radiography, abdominopelvic MRI, cystoscopy and proctoscopy if there was a clinical suspicion of invasion. Neoadjuvant chemoradiotherapy followed by radical surgery for locally advanced stage has been performed, as previously described [8]. After the end of chemoradiation, clinical response has been based on a second MRI and clinical examination and SCC serum levels. Clinical responders underwent radical surgery. Disease-free survival was calculated from the date of surgery to the date of relapse or the date of the last follow-up. Medians and life tables were computed using the product limit estimate by Kaplan–Meier methods and the log-rank test was used to assess the statistical significance [9].
Results Among 134 abstracts resulting from Medline research, 13 were deemed potentially relevant to the study questions. Three of them were updates of previous series, and they have been considered once. Thus, 10 original articles met criteria for full text review and are summarized below. Studies on surgical technique and feasibility or not specifically focused on cervical cancer staging have been excluded. Intraperitoneal spread of the disease and lymphnodal involvement have been the main objectives of the study. In fact, in our experience, clinical evaluation of the pelvis (i.e. diffusion to the vagina, vesicovaginal or recto-vaginal septums and cardinal ligament) is usually confirmed by histological evaluation. Preliminary data on pre-treatment staging laparoscopy were reported by Querleu et al. [4], on 39 early stage cervical cancer patients submitted to pelvic lymphadenectomy. Since then, several authors have investigated the role of laparoscopy in pretreatment surgical staging of cervical cancer. Childers et al. [10] described laparoscopic para-aortic lymph node sampling in 21 locally advanced cervical cancer in which CT predicted the presence of only 1 of 6 lymph node metastases. Other papers reported that pelvic nodal metastases were diagnosed in 3 out of 12 IB2 cervical cancer patients (25%), all of whom with negative computerized tomography (CT) scans prior to surgery [11]. In the same years, the role of pre-treatment of laparoscopic staging was published on a larger series of 84 LACC cases [12], including the following procedures: peritoneal washing for cytology, whole abdominal cavity exploration and biopsy of suspicious lesions, exploration of vesicocervical and rectovaginal septums with a biopsy of suspicious areas, bilateral pelvic lymphadenectomy and, when macroscopically positive, paraaortic lymphadenectomy. Eighteen out of 38 CTnegative pelvic node patients had nodal metastases (36.7% CT false negatives), whereas 5 out of 11 CT-suspicious pelvic node patients had nodal metastases (10.2% CT false positives). In addiction, 4.7% of patients presented with intraperitoneal spread of the disease. The authors concluded that laparoscopic staging is an effective and safe method in cervix uteri carcinoma, with a low incidence of complications and fast post-operative recovery, that does not delay the beginning of subsequent treatment. Moreover, it allows to tailor the treatment for each patient and to compare results obtained with different therapeutic approaches. In another series of LACC patients, peritoneal spread by laparoscopy was found in 29% of cases (16 out of 56) [13]. Vergote et al. [14] have reported about 18% of CT-false negative paraaortic lymph nodes in 38 consecutive stage IB2-III cervical cancer patients submitted to transperitoneal/extraperitoneal laparoscopic lymphadenectomy. A comparison between laparoscopic/histopathologic evaluation of tumor involvement of the para-aortic and pelvic lymph nodes, bladder wall and rectal pillar with preoperative findings of MRI and/or CT was performed in 109 untreated patients with cervical cancer FIGO IB2 and higher [7]. For pelvic nodes, CTfalse negatives and positives were 22.7% and 10.7%, whereas MRI-false negatives and positives were 13.4% and 10.4%. As far as aortic nodes are concerned, CT-false negatives and
A. Fagotti et al. / Gynecologic Oncology 107 (2007) S101–S105 Table 1 Results of pre-treatment laparoscopic staging in the evaluation of intraperitoneal disease in LACC patients Author (year)
All cases
Positive cases (%)
Vidaurreta (1999) Benedetti-Panici (1999) Hertel (2002) Marnitz (2005) Leblanc (2005)
84 59 101 84 156
4 (4.7) 15 (27.0) 3 (2.9) 15 (17.8) 3 (1.9)
positives were 14.3% and 9.9%, whereas MRI-false negatives and positives were 8.6% and 1.5%. Overall, false-negative or -positive results of MRI and CT imaging were proved on the basis of laparoscopic findings in 24 (22%) patients and led to a change in treatment plans. In particular, in 10 patients with false positive paraaortic lymph node metastases, extended field radiotherapy was shifted to 8 primary surgery and 2 teletherapy to the pelvis exclusively. On the other hand, 14 patients candidate to primary surgery were changed to chemotherapy for intraperitoneal metastases (2 cases) (palliative setting) and combined radiochemotherapy in 12 cases (positive para-aortic lymph nodes which had been negative by imaging techniques). When a more selected population was analyzed, an upstaging had to be done in 87% of 84 LACC patients. However, considering the whole population and including lymph nodal status in the staging, 134 out of 406 (33%) patients were allocated to a higher stage. In a randomized trial comparing surgical (extraperitoneal or laparoscopic) and clinical staging in 61 locally advanced cervical cancer patients [15], paraaortic lymph node metastases were documented in 25% of patients by histopathologic evaluation. Patients staged surgically had significantly worse progression-free survival than those without surgical staging, with hazard ratios of relapse/persistence and death of 3.13 (P = 0.005) and 1.76 (P = 0.150), respectively. It is concluded that the benefit of pre-treatment surgical staging of patients with cervical cancer remains unproven, suggesting a surgery-induced suppression of immune function in these patients. Extraperitoneal approach has been proposed for laparoscopic lymphadenectomy in 156 patients with bulky or locally advanced cervical cancer [16,17]. Three patients (1.9%) had peritoneal carcinomatosis, whereas an overall incidence of 25.4% of positive paraaortic lymph nodes was observed. These results impacted on further management. Two percent of patients were managed with
Table 2 Results of pre-treatment laparoscopic staging in the evaluation of aortic lymph nodal status in clinically node-negative LACC patients Author (year)
Negative imaging (CT/MRI)
All cases
Stage
Positive-histology by LPS Nr. (%)
Vergote (2002) Hertel (2002) Lai (2003) Chung (2005) LeBlanc (2005)
Aortic Aortic Aortic Aortic Aortic
38 91⁎ 32 44 156
IB2-IIIB ≥IB2 IIB-IVA IB2-IVA IB2-IVA
7 (18.4) 13 (14.3) 8 (25.0) 5 (11.3) 39 (25.4)
* Only cases staged by preoperative CT.
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Table 3 Patient's characteristics Clinical characteristics
Nr. (%)
Age (years) Median (range) FIGO Stage IB2–IIA IIB III–IVA Histotype Squamous Adenocarcinoma/adenosquamous Tumor volume (cm) ≥4 Node status (MRI) Positive Grade G1–2 G3
53 (25–80) 10 (6.6) 112 (73.7) 30 (19.7) 143 (94.0) 9 (6.0) 118 (77.6) 59 (38.8) 62 (41.0) 90 (59.0)
full dose chemotherapy, 24% stage IB2 required an extended field radiation therapy while stage II–IV could be managed with pelvic radiation only. Five-year disease-free survival was 54.2%, with a median follow-up of 30.1 months. The sensitivity, specificity, positive- and negative-predictive value of MRI in the assessment of para-aortic and pelvic LN involvement, when the pathologic diagnosis was taken as the gold standard, have been 55.9%, 79.6%, 48.7% and 83.9%, respectively, in 44 Korean LACC patients (77.3% IIB) [18]. The 2-year disease-free survival rate was 89.7%, with 3 cases of recurrence identified in a median follow-up of 19 months. Overall, the percentages of intraperitoneal spread of disease in different series of patients ranged between 1.9% and 27% (Table 1), whereas the rates of microscopic positive aortic nodes in clinically node-negative LACC varied between 11.3% and 25.4% (Table 2). In our Division, 152 LACC patients have been treated between October 1997 and February 2007. Patient characteristics are shown in Table 3. None of the patients has been submitted to pretreatment laparoscopic staging, whereas in all cases a preoperative MRI imaging has been performed. With a median follow-up of 28.0 months (range 3–126 months), 31 recurrences have been observed. The 5-year DFS has been 83% and OS 90%. These results are similar to those reported for patients submitted to pre-treatment laparoscopic staging (Table 4).
Table 4 Disease-free survival in surgically and clinically staged LACC patients Author (year)
Pre-treatment All Stage laparoscopic cases staging
Median DFS FU
Vergote (2002) Lai (2003) Chung (2005) LeBlanc (2005) Lai (2003) Scambia (2007)
Yes Yes Yes Yes No No
15 – 19.0 30.1 – 25.5
42 42 44 156 31 138
IB2–III IIB–IIIA IB2–IIIB IB2–IVA IIB–IIIA IIB–IVA
33–88% (1 year) 30% (5 years) 89.7 (2 years) 54.2% (5 years) 68% (5 years) 75% (5 years)
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Discussion The principal route of diffusion of cervical cancer is lymphatic. In fact, it is well known that patients with cervical cancer often have lymph node metastases, in a range variable according to the stage of the disease, between 5% and 19% in stage I to 34% and 70% in stage IV [19]. The occurrence of lymph node metastases appears to be the most important factor of overall survival and recurrence in these patients [20]. Imaging techniques, especially MRI, show high accuracy when predicting lymph node involvement (80%–93%) [21], but the limit is represented by the differentiation of tumor-involved or hyperplastic lymph node, which needs the expertise of a dedicated radiologist. The presence of micrometastases is another intrinsic obstacle to the optimal performance of MRI. Similar results have been obtained in the evaluation of parametrial, vaginal and septum status, but dubious cases can be easier resolved by clinical examination. The clinical value of FDG-PET for primary staging seems promising in locally advanced cervical cancer, with a sensitivity of 75–85.7%, specificity of 92–94.4% and accuracy of 92% [22,23]. In contrast, its value in primary, nonbulky, early stage and MRI-defined, LN-negative cervical cancer is questionable [24]: of 60 patients analyzed, 10 (16.7%) had pelvic LN metastases and one (1.7%) had para-aortic LN metastasis histologically. FDGPET detected the single PALN metastasis (1/1, 100%), but detected only 1/10 (10%) of the pelvic LN metastases. In this context, surgical staging of the pelvic/para-aortic nodes seems to overcome the percentage of undiagnosed node positive patients, which is still insuperable, independently from the preoperative staging technique used. However, the key questions to answer before accepting the routine use of surgical staging in the management of cervical cancer patients are the following: which is the price of the procedure? Which is the impact on treatment plan? And, more importantly, which is the real benefit in terms of survival? For a long time, one of the concern for surgical staging has been the complication rate associated to laparotomy. It is stated that laparoscopy leads to fewer postoperative adhesion formations, which could partially prevent post-operative radiotherapeutic effects [3,5]. Moreover, employing an extraperitoneal approach rather than a transperitoneal one can decrease the enteric complications secondary to intra-abdominal adhesion formation [16,17]. The combination of laparoscopy with an extraperitoneal approach in the staging of cervical cancer combines the benefits of these minimally invasive techniques. It includes advantages of previous surgical adhesions, decreased risk of electrosurgical bowel injury or enterotomy, and allows patients starting subsequent radiation therapy immediately. Finally, laparoscopic lymph node dissection has been shown to be comparable to laparotomy in terms of node counts [6]. Data reported in the literature have clearly demonstrated that surgical staging offers the possibility to identify a percentage of node-positive cases, which are missed by pre-operative imaging staging. However, the consequent changes of the treatment plan can differ, according to treatment strategies adopted in different centers. For instance, in early-stage disease, we usually perform
radical hysterectomy plus transperitoneal systematic pelvic and para-aortic lymphadenectomy, in the case of positive pelvic nodes or suspicious aortic nodes at pre-operative imaging or intraoperatively [25]. Thus, the evidence of positive nodes does not change the decision of immediate radical surgery, but only the need of adjuvant therapy. For this reason, the analysis has been focused on LACC patients, only. The percentage of aortic positive nodes in clinically negative cases has been reported between 11% and 25%, by laparoscopy. In these cases, the presence of silent microscopic positive nodes in the aortic region can modify the treatment plan scheduled which included standard pelvic chemoradiation, versus extended field radiotherapy or neoadjuvant chemotherapy followed by radical surgery. Nevertheless, we know that the detection of such metastases does not result automatically in a cure, since prophylactic extended-field irradiation to cover both para-aortic lymph node and whole pelvis in comparison with pelvis alone have failed to prove conclusive benefits [26–28]. Thus, who are those patients who need special treatment strategy for occult para-aortic node metastases? Lai's randomized study [15] showed paraaortic lymph node metastases in 25% of patients staged surgically, but all had significantly worse progression-free survival than those without surgical staging. Although some limitation can be ascribed to the study, such as the long time interval between surgical staging and radiotherapy and the low number of harvested LNs, the therapeutic benefit of surgical staging has still to be demonstrated, to date. In 152 LACC patients treated at the Division of Gynecologic Oncology of the Catholic University of Rome and Campobasso, staged only by pre-operative MRI and gynecological examination under general anesthesia, the 5-year DFS has been 83% (median follow-up 28.0 months, range 3–126). Although only a retrospective analysis can be carried out, such result well compares to cases surgically staged. It remains to clarify whether such good results are due to an accurate clinical staging or to the choice of a multimodal treatment [8]. The presence of intraperitoneal diffusion of disease can be recognized in LACC cases in a percentage ranging between 1.9% and 29% [3,7,12]. These patients can be submitted to salvage-
Fig. 1. Impact of pre-treatment laparoscopic staging in the management of LACC patients.
A. Fagotti et al. / Gynecologic Oncology 107 (2007) S101–S105
treatment by systemic chemotherapy with low benefit in terms of DFS. A translation of these results can be summarized in Fig. 1. However, pre-operative surgical staging can theoretically offer an advantage in terms of survival, via the debulking of macroscopically positive nodes. As reported previously, the survival of patients with completely resected LNs with macroscopic disease was similar to that of women with microscopic disease in previous studies [25,29,30]. More recently, Marnitz et al. [3] found that the laparoscopic removal of more than five pelvic and/or more than five para-aortic lymph nodes was associated with significantly longer survival and it should be done prior to primary chemoradiation in patients with LACC. Finally, another advantage of pre-treatment laparoscopic staging in young patients with advanced cervical cancer is the transposition of the ovary outside the radiation field during LND to preserve ovarian function and even fertility in very selected cases with small tumors (b3 cm) without extrauterine disease or uterine involvement and LVSI [31]. In conclusion, pre-treatment surgical staging can identify positive nodes in LACC patients considered clinically negative, and recognize intraperitoneal disease, thus making the physician tailor the treatment on the bases of histopathological result. Moreover, it offers the potential advantage of debulking of macroscopically positive nodes, and to transpose the ovary outside the radiation field to preserve ovarian function and even fertility. However, the positive impact on DFS has still to be demonstrated. Conflict of interest statement We declare that we have no conflict of interest.
References [1] Amendola MA, Hricak H, Mitchell DG, Snyder B, Chi DS, Long III HJ, et al. Utilization of diagnostic studies in the pretreatment evaluation of invasive cervical cancer in the United States: results of intergroup protocol ACRIN 6651/GOG 183. J Clin Oncol 2005;23:7454–9. [2] Choi HJ, Roh JW, Seo SS, Lee S, Kim JY, Kim SK, et al. Comparison of the accuracy of magnetic resonance imaging and positron emission tomography/ computed tomography in the presurgical detection of lymph node metastases in patients with uterine cervical carcinoma. Cancer 2006;106:914–22. [3] Marnitz S, Kohler C, Roth C, Fuller J, Hinkelbein W, Schneider A. Is there a benefit of pretreatment laparoscopic transperitoneal surgical staging in patients with advanced cervical cancer? Gynecol Oncol 2005;99:536–44. [4] Querleu D, Leblanc E, Castelain B. Laparoscopic pelvic lymphadenectomy in the staging of early carcinoma of the cervix. Am J Obstet Gynecol 1991;164:579–81. [5] Goff BA, Muntz HG, Paley PJ, Tamimi HK, Koh W, Green BE. Impact of surgical staging in women with locally advanced cervical cancer. Gynecol Oncol 1999;74:436–42. [6] Kohler C, Klemm P, Schau A, Possover M, Krause N, Tozzi R, et al. Introduction of transperitoneal lymphadenectomy in a gynecologic oncology center: analysis of 650 laparoscopic pelvic and/or paraaortic transperitoneal lymphadenectomies. Gynecol Oncol 2004;95:52–61. [7] Hertel H, Kohler C, Elhawary T, Michels W, Possover M, Schneider A. Laparoscopic staging compared with imaging techniques in the staging of advanced cervical cancer. Gynecol Oncol 2002;87:46–51. [8] Di Stefano MG, Fagotti A, Ferrandina G, Fanfani F, Smaniotto D, D'Agostino G, et al. Preopeartive chemoradiotherapy in locally advanced cervical cancer: long term outcome and complications. Gynecol Oncol 2005;99:S166–70. [9] Mantel N. Evaluation of survival data and two new rank order statistics arising its consideration. Cancer Chemother Rep 1996;50:163–70.
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[10] Childers JM, Hatch K, Surwit EA. The role of laparoscopic lymphadenectomy in the management of cervical carcinoma. Gynecol Oncol 1992;47:38–43. [11] Recio FO, Piver MS, Hempling RE. Pretreatment transperitoneal laparoscopic staging pelvic and paraaortic lymphadenectomy in large (N or =5 cm) stage IB2 cervical carcinoma: report of a pilot study. Gynecol Oncol 1996;63:333–6. [12] Vidaurreta J, Bermudez A, di Paola G, Sardi J. Laparoscopic staging in locally advanced cervical carcinoma: a new possible philosophy? Gynecol Oncol 1999;75:366–71. [13] Benedetti-Panici P, Maneschi F, Cutillo G, Congiu M, Franchi M, Amoroso M, et al. Laparoscopic abdominal staging in locally advanced cervical cancer. Int J Gynecol Cancer 1999;9:194–7. [14] Vergote I, Amant F, Berteloot P, Van Gramberen M. Laparoscopic lower para-aortic staging lymphadenectomy in stage IB2, II, and III cervical cancer. Int J Gynecol Cancer 2002;12:22–6. [15] Lai CH, Huang KG, Hong JH, Lee CL, Chou HH, Chang TC, et al. Randomized trial of surgical staging (extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer. Gynecol Oncol 2003;89:160–7. [16] Sonoda Y, Leblanc E, Querleu D, Castelain B, Papageorgiou TH, Lambaudie E, et al. Prospective evaluation of surgical staging of advanced cervical cancer via a laparoscopic extraperitoneal approach. Gynecol Oncol 2003;91:326–31. [17] Leblanc F, Narducci F, Chevalier A, Taieb S, Castelain B, Querleu D. Pretherapeutic laparoscopic staging of locally advanced cervical carcinomas: technique and results. Gynecol Oncol 2005;99:S157–8. [18] Chung HH, Lee S, Sim JS, Kim JY, et al. Pretreatment laparoscopic surgical staging in locally advanced cervical cancer: preliminary results in Korea. Gynecol Oncol 2005;97:468–75. [19] Stehman FB, Perez CA, Kurman RJ, Thigpen JT. Uterine cervix. In: Hoskins WJ, Perez CA, Young RC, editors. Gynecologic oncology. 2nd ed. Philadelphia: Lippincott-Raven; 1997. p. 785–857. [20] Tanaka Y, Sawada S, Murata T. Relationship between lymph node metastases and prognosis in patients irradiated postoperatively for carcinoma of the uterine cervix. Acta Radiol Oncol 1984;23:455–9. [21] Rockall AG, Sohaib SA, Harisinghani MG, Babar SA, Singh N, Jeyarajah AR, et al. Diagnostic performance of nanoparticle-enhance magnetic resonance imaging in the diagnosis of lymphnode metastases in patients with endometrial and cervical cancer. J Clin Oncol 2005;23:2813–21. [22] Lin WC, Hung YC, Yeh LS, Kao CH, Yen RF, Shen YY. Usefulness of (18)F-fluorodeoxyglucose positron emission tomography to detect paraaortic lymph nodal metastasis in advanced cervical cancer with negative computed tomography findings. Gynecol Oncol 2003;89:73–6. [23] Rose PG, Adler LP, Rodriguez M, Faulhaber PF, Abdul-Karim FW, Miraldi F. Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: a surgicopathologic study. J Clin Oncol 1999;17:41–5. [24] Chou HH, Chang TC, Yen TC, Ng KK, Hsueh S, Ma SY, et al. Low value of 18F-Fluoro-2-Doexy-D-Glucose Positron Emission Tomography in primary staging of early stage cervical cancer before radical hysterectomy. J Clin Oncol 2006;24:123–8. [25] Hacker NF, Wain GV, Nicklin JL. Resection of bulky positive lymph nodes in patients with cervical carcinoma. Int J Gynecol Cancer 1995;5:250–6. [26] Rotman M, Pajak TF, Choi K, Clery M, Marcial V, Grigsby PW, et al. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. J Am Med Assoc 1995;274:387–93. [27] Grisby PW, Heydon K, Mutch DG, Kim RY, Eifel P. Long-term follow-up o RTOG 92-10: cervical cancer with positive para-aortic lymph nodes. Int J Radiat Oncol Biol Phys 2001;51:982–7. [28] Eifel PJ, Winter K, Morris M, Levemback C, Grisby PW, Cooper J, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and paraaortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 2004;22:872–80. [29] Cosin JA, Fowler JM, Chen MD, Paley PJ, Carson LF, Twiggs LB. Pretreatment surgical staging of patients with cervical carcinoma: the case for lymph node debulking. Cancer 1998;82:2241–8. [30] Kupets R, Thomas GM, Covens A. Is there a role for pelvic lymph node debulking in advanced cervical cancer? Gynecol Oncol 2002;87:163–70. [31] Morice P, Castaigne D. New approaches in “conventional” surgery of uterine cervix cancer. Cancer Radiother 2000;4:122–6.
Which role for pre-treatment laparoscopic staging? Anna Fagotti a , Francesco Fanfani a , Romina Longo a , Francesco Legge a , Alessandra Mari a , Maria L. Gagliardi a , Giovanni Scambia a,b,⁎ a
Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Campobasso, Italy b Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy Received 6 July 2007 Available online 28 August 2007
Abstract Objective. To investigate in cervical cancer patients the impact of pre-treatment laparoscopic staging on treatment plan and disease free survival. Methods. A review of the present literature has been performed and data have been compared to results obtained in a large series of patients not surgically staged. Results. Among 134 abstracts resulting from Medline research, 13 were deemed potentially relevant to the study questions. The presence of intraperitoneal diffusion of disease can be recognized in locally advanced cervical cancer patients (LACC) in a percentage ranging between 1.9% and 29%. The rate of aortic positive nodes in clinically negative LACC patients cases has been reported between 11% and 25%, by laparoscopy. In our Division, 152 LACC patients have been treated between October 1997 and February 2007. None of the patients has been submitted to pretreatment laparoscopic staging, whereas in all cases a pre-operative MRI has been performed. With a median follow-up 28.0 months (range 3– 126 months), 31 recurrences have been observed. The 5-year DFS has been 83% and OS 90%. Although only a retrospective analysis can be carried out, such result well compares to cases surgically staged. Conclusions. Pre-treatment surgical staging can identify positive nodes in LACC patients considered clinically negative, and recognize intraperitoneal disease, thus making the physician tailor the treatment on the bases of histopathological result. Moreover, it offers the potential advantage of debulking of macroscopically positive nodes, and to transpose the ovary outside the radiation. However, the positive impact on DFS has still to be demonstrated. © 2007 Elsevier Inc. All rights reserved. Keywords: Laparoscopy; Cervical cancer; Staging
Introduction Treatment of cervical cancer greatly varies according to the stage of the disease, consisting in immediate radical surgery, exclusive chemoradiation or neoadjuvant treatment followed by radical surgery. However, despite the impact of the stage of disease on the treatment plan, cervical cancer staging is based on clinical rather than surgical assessment. This means that the extent of the disease is evaluated by the physical examination
⁎ Corresponding author. Gynecologic Oncology Unit, Catholic University, L.go A. Gemelli, 8 00168, Rome, Italy. Fax: +39 0635508736. E-mail address: [email protected] (G. Scambia). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.07.005
under anesthesia and a few other tests that are done in some cases, such as cystoscopy and proctoscopy. Among possible sites of diffusion, lymphnodal status or tumor spread within the abdominal cavity and the peritoneal surface are certainly the most difficult variables to evaluate by clinical examination with respect to a possible infiltration of the parametrium, vagina, the vesico-vaginal or recto-vaginal septum. Moreover, detection of metastatic paraaortic nodes or peritoneal carcinosis may lead to a change in the treatment plan. Although not recognized by FIGO, computed tomography (CT) and magnetic resonance imaging (MRI) are widely used for therapeutic decisions in patients with cervical cancer, with a large discrepancy between FIGO recommendations and the actual test used for cervical cancer staging [1]. However,
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correlation of CT and MRI findings with histopathological evaluation of surgical specimen is variable [2]. Surgical staging is the ideal method to determine the extent of the disease outside the cervix, vagina and parametria. The advantages of surgical exploration can be: detection of intrabdominal disease, assessment of pathological status of lymph nodes and vesico-vaginal or recto-vaginal septum and debulking of tumor involved nodes [3]. Recently, it has been shown that pre-treatment laparoscopic staging does not increase morbidity, and it has the additional advantage of less postoperative adhesion formations respect to laparotomy [4,5]. Paraaortic and pelvic lymphadenectomy can be done safely laparoscopically and can be considered as complete as by open surgery [6], and tumor invasion into the vesicocervical ligament, the rectovaginal septum or intraperitoneally can be also detected [7]. The aim of this study was to investigate in cervical cancer patients the impact of pre-treatment laparoscopic staging on treatment plan and disease free survival. To this purpose, a review of the present literature has been performed and data have been compared to results obtained in a large series of patients not surgically staged. Materials and methods A systematic review of the literature on pre-treatment laparoscopic surgical staging in cervical cancer patients has been performed until April 2003. Filters and limitations have been used to eliminate inappropriate publications. General inclusion criteria have been applied to maximize the applicability of the search results. The search strategy has combined the concepts of cervical cancer and staging laparoscopy. After filtering irrelevant publication, individual review of the abstracts has been performed to identify articles for full review. Inclusion criteria have been used for accepting studies, as follows: (1) English or French language articles reporting primary data and published in a peer review journal (not abstracts); (2) studies that include a consistent number of patients with cervical cancer undergoing staging laparoscopy. A second level of inclusion criteria has been applied to all articles identified for full text review based on a review of the abstracts. Prior to full text review, these articles have been screened to ensure that they answer the study question: impact on treatment plan and survival. Data on patient population characteristics, laparoscopic technique for staging, complications, treatment plan and follow-up have been abstracted. In addition to the above criteria used to describe an ideal study design, additional criteria for determining the quality of a given study have been developed and applied during data abstraction. These criteria have been as follows: (1) the study had a representative sample, (2) the setting and selection of the population under investigation were clearly described, (3) the study design minimized differences between patients who received the tests and (4) histopathological or clinical confirmation of disease were mentioned. Each article was reviewed by at least two reviewers. Discrepancies between reviewers were resolved by consensus. Our study population consists of 152 consecutive patients with histologically proven locally advanced cervical cancer (LACC) accrued between October 1997 and February 2007 at the Divisions of Gynecologic Oncology of the Catholic University of Rome and Campobasso. Pre-treatment work up included a medical history, clinical examination under anesthesia, chest radiography, abdominopelvic MRI, cystoscopy and proctoscopy if there was a clinical suspicion of invasion. Neoadjuvant chemoradiotherapy followed by radical surgery for locally advanced stage has been performed, as previously described [8]. After the end of chemoradiation, clinical response has been based on a second MRI and clinical examination and SCC serum levels. Clinical responders underwent radical surgery. Disease-free survival was calculated from the date of surgery to the date of relapse or the date of the last follow-up. Medians and life tables were computed using the product limit estimate by Kaplan–Meier methods and the log-rank test was used to assess the statistical significance [9].
Results Among 134 abstracts resulting from Medline research, 13 were deemed potentially relevant to the study questions. Three of them were updates of previous series, and they have been considered once. Thus, 10 original articles met criteria for full text review and are summarized below. Studies on surgical technique and feasibility or not specifically focused on cervical cancer staging have been excluded. Intraperitoneal spread of the disease and lymphnodal involvement have been the main objectives of the study. In fact, in our experience, clinical evaluation of the pelvis (i.e. diffusion to the vagina, vesicovaginal or recto-vaginal septums and cardinal ligament) is usually confirmed by histological evaluation. Preliminary data on pre-treatment staging laparoscopy were reported by Querleu et al. [4], on 39 early stage cervical cancer patients submitted to pelvic lymphadenectomy. Since then, several authors have investigated the role of laparoscopy in pretreatment surgical staging of cervical cancer. Childers et al. [10] described laparoscopic para-aortic lymph node sampling in 21 locally advanced cervical cancer in which CT predicted the presence of only 1 of 6 lymph node metastases. Other papers reported that pelvic nodal metastases were diagnosed in 3 out of 12 IB2 cervical cancer patients (25%), all of whom with negative computerized tomography (CT) scans prior to surgery [11]. In the same years, the role of pre-treatment of laparoscopic staging was published on a larger series of 84 LACC cases [12], including the following procedures: peritoneal washing for cytology, whole abdominal cavity exploration and biopsy of suspicious lesions, exploration of vesicocervical and rectovaginal septums with a biopsy of suspicious areas, bilateral pelvic lymphadenectomy and, when macroscopically positive, paraaortic lymphadenectomy. Eighteen out of 38 CTnegative pelvic node patients had nodal metastases (36.7% CT false negatives), whereas 5 out of 11 CT-suspicious pelvic node patients had nodal metastases (10.2% CT false positives). In addiction, 4.7% of patients presented with intraperitoneal spread of the disease. The authors concluded that laparoscopic staging is an effective and safe method in cervix uteri carcinoma, with a low incidence of complications and fast post-operative recovery, that does not delay the beginning of subsequent treatment. Moreover, it allows to tailor the treatment for each patient and to compare results obtained with different therapeutic approaches. In another series of LACC patients, peritoneal spread by laparoscopy was found in 29% of cases (16 out of 56) [13]. Vergote et al. [14] have reported about 18% of CT-false negative paraaortic lymph nodes in 38 consecutive stage IB2-III cervical cancer patients submitted to transperitoneal/extraperitoneal laparoscopic lymphadenectomy. A comparison between laparoscopic/histopathologic evaluation of tumor involvement of the para-aortic and pelvic lymph nodes, bladder wall and rectal pillar with preoperative findings of MRI and/or CT was performed in 109 untreated patients with cervical cancer FIGO IB2 and higher [7]. For pelvic nodes, CTfalse negatives and positives were 22.7% and 10.7%, whereas MRI-false negatives and positives were 13.4% and 10.4%. As far as aortic nodes are concerned, CT-false negatives and
A. Fagotti et al. / Gynecologic Oncology 107 (2007) S101–S105 Table 1 Results of pre-treatment laparoscopic staging in the evaluation of intraperitoneal disease in LACC patients Author (year)
All cases
Positive cases (%)
Vidaurreta (1999) Benedetti-Panici (1999) Hertel (2002) Marnitz (2005) Leblanc (2005)
84 59 101 84 156
4 (4.7) 15 (27.0) 3 (2.9) 15 (17.8) 3 (1.9)
positives were 14.3% and 9.9%, whereas MRI-false negatives and positives were 8.6% and 1.5%. Overall, false-negative or -positive results of MRI and CT imaging were proved on the basis of laparoscopic findings in 24 (22%) patients and led to a change in treatment plans. In particular, in 10 patients with false positive paraaortic lymph node metastases, extended field radiotherapy was shifted to 8 primary surgery and 2 teletherapy to the pelvis exclusively. On the other hand, 14 patients candidate to primary surgery were changed to chemotherapy for intraperitoneal metastases (2 cases) (palliative setting) and combined radiochemotherapy in 12 cases (positive para-aortic lymph nodes which had been negative by imaging techniques). When a more selected population was analyzed, an upstaging had to be done in 87% of 84 LACC patients. However, considering the whole population and including lymph nodal status in the staging, 134 out of 406 (33%) patients were allocated to a higher stage. In a randomized trial comparing surgical (extraperitoneal or laparoscopic) and clinical staging in 61 locally advanced cervical cancer patients [15], paraaortic lymph node metastases were documented in 25% of patients by histopathologic evaluation. Patients staged surgically had significantly worse progression-free survival than those without surgical staging, with hazard ratios of relapse/persistence and death of 3.13 (P = 0.005) and 1.76 (P = 0.150), respectively. It is concluded that the benefit of pre-treatment surgical staging of patients with cervical cancer remains unproven, suggesting a surgery-induced suppression of immune function in these patients. Extraperitoneal approach has been proposed for laparoscopic lymphadenectomy in 156 patients with bulky or locally advanced cervical cancer [16,17]. Three patients (1.9%) had peritoneal carcinomatosis, whereas an overall incidence of 25.4% of positive paraaortic lymph nodes was observed. These results impacted on further management. Two percent of patients were managed with
Table 2 Results of pre-treatment laparoscopic staging in the evaluation of aortic lymph nodal status in clinically node-negative LACC patients Author (year)
Negative imaging (CT/MRI)
All cases
Stage
Positive-histology by LPS Nr. (%)
Vergote (2002) Hertel (2002) Lai (2003) Chung (2005) LeBlanc (2005)
Aortic Aortic Aortic Aortic Aortic
38 91⁎ 32 44 156
IB2-IIIB ≥IB2 IIB-IVA IB2-IVA IB2-IVA
7 (18.4) 13 (14.3) 8 (25.0) 5 (11.3) 39 (25.4)
* Only cases staged by preoperative CT.
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Table 3 Patient's characteristics Clinical characteristics
Nr. (%)
Age (years) Median (range) FIGO Stage IB2–IIA IIB III–IVA Histotype Squamous Adenocarcinoma/adenosquamous Tumor volume (cm) ≥4 Node status (MRI) Positive Grade G1–2 G3
53 (25–80) 10 (6.6) 112 (73.7) 30 (19.7) 143 (94.0) 9 (6.0) 118 (77.6) 59 (38.8) 62 (41.0) 90 (59.0)
full dose chemotherapy, 24% stage IB2 required an extended field radiation therapy while stage II–IV could be managed with pelvic radiation only. Five-year disease-free survival was 54.2%, with a median follow-up of 30.1 months. The sensitivity, specificity, positive- and negative-predictive value of MRI in the assessment of para-aortic and pelvic LN involvement, when the pathologic diagnosis was taken as the gold standard, have been 55.9%, 79.6%, 48.7% and 83.9%, respectively, in 44 Korean LACC patients (77.3% IIB) [18]. The 2-year disease-free survival rate was 89.7%, with 3 cases of recurrence identified in a median follow-up of 19 months. Overall, the percentages of intraperitoneal spread of disease in different series of patients ranged between 1.9% and 27% (Table 1), whereas the rates of microscopic positive aortic nodes in clinically node-negative LACC varied between 11.3% and 25.4% (Table 2). In our Division, 152 LACC patients have been treated between October 1997 and February 2007. Patient characteristics are shown in Table 3. None of the patients has been submitted to pretreatment laparoscopic staging, whereas in all cases a preoperative MRI imaging has been performed. With a median follow-up of 28.0 months (range 3–126 months), 31 recurrences have been observed. The 5-year DFS has been 83% and OS 90%. These results are similar to those reported for patients submitted to pre-treatment laparoscopic staging (Table 4).
Table 4 Disease-free survival in surgically and clinically staged LACC patients Author (year)
Pre-treatment All Stage laparoscopic cases staging
Median DFS FU
Vergote (2002) Lai (2003) Chung (2005) LeBlanc (2005) Lai (2003) Scambia (2007)
Yes Yes Yes Yes No No
15 – 19.0 30.1 – 25.5
42 42 44 156 31 138
IB2–III IIB–IIIA IB2–IIIB IB2–IVA IIB–IIIA IIB–IVA
33–88% (1 year) 30% (5 years) 89.7 (2 years) 54.2% (5 years) 68% (5 years) 75% (5 years)
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Discussion The principal route of diffusion of cervical cancer is lymphatic. In fact, it is well known that patients with cervical cancer often have lymph node metastases, in a range variable according to the stage of the disease, between 5% and 19% in stage I to 34% and 70% in stage IV [19]. The occurrence of lymph node metastases appears to be the most important factor of overall survival and recurrence in these patients [20]. Imaging techniques, especially MRI, show high accuracy when predicting lymph node involvement (80%–93%) [21], but the limit is represented by the differentiation of tumor-involved or hyperplastic lymph node, which needs the expertise of a dedicated radiologist. The presence of micrometastases is another intrinsic obstacle to the optimal performance of MRI. Similar results have been obtained in the evaluation of parametrial, vaginal and septum status, but dubious cases can be easier resolved by clinical examination. The clinical value of FDG-PET for primary staging seems promising in locally advanced cervical cancer, with a sensitivity of 75–85.7%, specificity of 92–94.4% and accuracy of 92% [22,23]. In contrast, its value in primary, nonbulky, early stage and MRI-defined, LN-negative cervical cancer is questionable [24]: of 60 patients analyzed, 10 (16.7%) had pelvic LN metastases and one (1.7%) had para-aortic LN metastasis histologically. FDGPET detected the single PALN metastasis (1/1, 100%), but detected only 1/10 (10%) of the pelvic LN metastases. In this context, surgical staging of the pelvic/para-aortic nodes seems to overcome the percentage of undiagnosed node positive patients, which is still insuperable, independently from the preoperative staging technique used. However, the key questions to answer before accepting the routine use of surgical staging in the management of cervical cancer patients are the following: which is the price of the procedure? Which is the impact on treatment plan? And, more importantly, which is the real benefit in terms of survival? For a long time, one of the concern for surgical staging has been the complication rate associated to laparotomy. It is stated that laparoscopy leads to fewer postoperative adhesion formations, which could partially prevent post-operative radiotherapeutic effects [3,5]. Moreover, employing an extraperitoneal approach rather than a transperitoneal one can decrease the enteric complications secondary to intra-abdominal adhesion formation [16,17]. The combination of laparoscopy with an extraperitoneal approach in the staging of cervical cancer combines the benefits of these minimally invasive techniques. It includes advantages of previous surgical adhesions, decreased risk of electrosurgical bowel injury or enterotomy, and allows patients starting subsequent radiation therapy immediately. Finally, laparoscopic lymph node dissection has been shown to be comparable to laparotomy in terms of node counts [6]. Data reported in the literature have clearly demonstrated that surgical staging offers the possibility to identify a percentage of node-positive cases, which are missed by pre-operative imaging staging. However, the consequent changes of the treatment plan can differ, according to treatment strategies adopted in different centers. For instance, in early-stage disease, we usually perform
radical hysterectomy plus transperitoneal systematic pelvic and para-aortic lymphadenectomy, in the case of positive pelvic nodes or suspicious aortic nodes at pre-operative imaging or intraoperatively [25]. Thus, the evidence of positive nodes does not change the decision of immediate radical surgery, but only the need of adjuvant therapy. For this reason, the analysis has been focused on LACC patients, only. The percentage of aortic positive nodes in clinically negative cases has been reported between 11% and 25%, by laparoscopy. In these cases, the presence of silent microscopic positive nodes in the aortic region can modify the treatment plan scheduled which included standard pelvic chemoradiation, versus extended field radiotherapy or neoadjuvant chemotherapy followed by radical surgery. Nevertheless, we know that the detection of such metastases does not result automatically in a cure, since prophylactic extended-field irradiation to cover both para-aortic lymph node and whole pelvis in comparison with pelvis alone have failed to prove conclusive benefits [26–28]. Thus, who are those patients who need special treatment strategy for occult para-aortic node metastases? Lai's randomized study [15] showed paraaortic lymph node metastases in 25% of patients staged surgically, but all had significantly worse progression-free survival than those without surgical staging. Although some limitation can be ascribed to the study, such as the long time interval between surgical staging and radiotherapy and the low number of harvested LNs, the therapeutic benefit of surgical staging has still to be demonstrated, to date. In 152 LACC patients treated at the Division of Gynecologic Oncology of the Catholic University of Rome and Campobasso, staged only by pre-operative MRI and gynecological examination under general anesthesia, the 5-year DFS has been 83% (median follow-up 28.0 months, range 3–126). Although only a retrospective analysis can be carried out, such result well compares to cases surgically staged. It remains to clarify whether such good results are due to an accurate clinical staging or to the choice of a multimodal treatment [8]. The presence of intraperitoneal diffusion of disease can be recognized in LACC cases in a percentage ranging between 1.9% and 29% [3,7,12]. These patients can be submitted to salvage-
Fig. 1. Impact of pre-treatment laparoscopic staging in the management of LACC patients.
A. Fagotti et al. / Gynecologic Oncology 107 (2007) S101–S105
treatment by systemic chemotherapy with low benefit in terms of DFS. A translation of these results can be summarized in Fig. 1. However, pre-operative surgical staging can theoretically offer an advantage in terms of survival, via the debulking of macroscopically positive nodes. As reported previously, the survival of patients with completely resected LNs with macroscopic disease was similar to that of women with microscopic disease in previous studies [25,29,30]. More recently, Marnitz et al. [3] found that the laparoscopic removal of more than five pelvic and/or more than five para-aortic lymph nodes was associated with significantly longer survival and it should be done prior to primary chemoradiation in patients with LACC. Finally, another advantage of pre-treatment laparoscopic staging in young patients with advanced cervical cancer is the transposition of the ovary outside the radiation field during LND to preserve ovarian function and even fertility in very selected cases with small tumors (b3 cm) without extrauterine disease or uterine involvement and LVSI [31]. In conclusion, pre-treatment surgical staging can identify positive nodes in LACC patients considered clinically negative, and recognize intraperitoneal disease, thus making the physician tailor the treatment on the bases of histopathological result. Moreover, it offers the potential advantage of debulking of macroscopically positive nodes, and to transpose the ovary outside the radiation field to preserve ovarian function and even fertility. However, the positive impact on DFS has still to be demonstrated. Conflict of interest statement We declare that we have no conflict of interest.
References [1] Amendola MA, Hricak H, Mitchell DG, Snyder B, Chi DS, Long III HJ, et al. Utilization of diagnostic studies in the pretreatment evaluation of invasive cervical cancer in the United States: results of intergroup protocol ACRIN 6651/GOG 183. J Clin Oncol 2005;23:7454–9. [2] Choi HJ, Roh JW, Seo SS, Lee S, Kim JY, Kim SK, et al. Comparison of the accuracy of magnetic resonance imaging and positron emission tomography/ computed tomography in the presurgical detection of lymph node metastases in patients with uterine cervical carcinoma. Cancer 2006;106:914–22. [3] Marnitz S, Kohler C, Roth C, Fuller J, Hinkelbein W, Schneider A. Is there a benefit of pretreatment laparoscopic transperitoneal surgical staging in patients with advanced cervical cancer? Gynecol Oncol 2005;99:536–44. [4] Querleu D, Leblanc E, Castelain B. Laparoscopic pelvic lymphadenectomy in the staging of early carcinoma of the cervix. Am J Obstet Gynecol 1991;164:579–81. [5] Goff BA, Muntz HG, Paley PJ, Tamimi HK, Koh W, Green BE. Impact of surgical staging in women with locally advanced cervical cancer. Gynecol Oncol 1999;74:436–42. [6] Kohler C, Klemm P, Schau A, Possover M, Krause N, Tozzi R, et al. Introduction of transperitoneal lymphadenectomy in a gynecologic oncology center: analysis of 650 laparoscopic pelvic and/or paraaortic transperitoneal lymphadenectomies. Gynecol Oncol 2004;95:52–61. [7] Hertel H, Kohler C, Elhawary T, Michels W, Possover M, Schneider A. Laparoscopic staging compared with imaging techniques in the staging of advanced cervical cancer. Gynecol Oncol 2002;87:46–51. [8] Di Stefano MG, Fagotti A, Ferrandina G, Fanfani F, Smaniotto D, D'Agostino G, et al. Preopeartive chemoradiotherapy in locally advanced cervical cancer: long term outcome and complications. Gynecol Oncol 2005;99:S166–70. [9] Mantel N. Evaluation of survival data and two new rank order statistics arising its consideration. Cancer Chemother Rep 1996;50:163–70.
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[10] Childers JM, Hatch K, Surwit EA. The role of laparoscopic lymphadenectomy in the management of cervical carcinoma. Gynecol Oncol 1992;47:38–43. [11] Recio FO, Piver MS, Hempling RE. Pretreatment transperitoneal laparoscopic staging pelvic and paraaortic lymphadenectomy in large (N or =5 cm) stage IB2 cervical carcinoma: report of a pilot study. Gynecol Oncol 1996;63:333–6. [12] Vidaurreta J, Bermudez A, di Paola G, Sardi J. Laparoscopic staging in locally advanced cervical carcinoma: a new possible philosophy? Gynecol Oncol 1999;75:366–71. [13] Benedetti-Panici P, Maneschi F, Cutillo G, Congiu M, Franchi M, Amoroso M, et al. Laparoscopic abdominal staging in locally advanced cervical cancer. Int J Gynecol Cancer 1999;9:194–7. [14] Vergote I, Amant F, Berteloot P, Van Gramberen M. Laparoscopic lower para-aortic staging lymphadenectomy in stage IB2, II, and III cervical cancer. Int J Gynecol Cancer 2002;12:22–6. [15] Lai CH, Huang KG, Hong JH, Lee CL, Chou HH, Chang TC, et al. Randomized trial of surgical staging (extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer. Gynecol Oncol 2003;89:160–7. [16] Sonoda Y, Leblanc E, Querleu D, Castelain B, Papageorgiou TH, Lambaudie E, et al. Prospective evaluation of surgical staging of advanced cervical cancer via a laparoscopic extraperitoneal approach. Gynecol Oncol 2003;91:326–31. [17] Leblanc F, Narducci F, Chevalier A, Taieb S, Castelain B, Querleu D. Pretherapeutic laparoscopic staging of locally advanced cervical carcinomas: technique and results. Gynecol Oncol 2005;99:S157–8. [18] Chung HH, Lee S, Sim JS, Kim JY, et al. Pretreatment laparoscopic surgical staging in locally advanced cervical cancer: preliminary results in Korea. Gynecol Oncol 2005;97:468–75. [19] Stehman FB, Perez CA, Kurman RJ, Thigpen JT. Uterine cervix. In: Hoskins WJ, Perez CA, Young RC, editors. Gynecologic oncology. 2nd ed. Philadelphia: Lippincott-Raven; 1997. p. 785–857. [20] Tanaka Y, Sawada S, Murata T. Relationship between lymph node metastases and prognosis in patients irradiated postoperatively for carcinoma of the uterine cervix. Acta Radiol Oncol 1984;23:455–9. [21] Rockall AG, Sohaib SA, Harisinghani MG, Babar SA, Singh N, Jeyarajah AR, et al. Diagnostic performance of nanoparticle-enhance magnetic resonance imaging in the diagnosis of lymphnode metastases in patients with endometrial and cervical cancer. J Clin Oncol 2005;23:2813–21. [22] Lin WC, Hung YC, Yeh LS, Kao CH, Yen RF, Shen YY. Usefulness of (18)F-fluorodeoxyglucose positron emission tomography to detect paraaortic lymph nodal metastasis in advanced cervical cancer with negative computed tomography findings. Gynecol Oncol 2003;89:73–6. [23] Rose PG, Adler LP, Rodriguez M, Faulhaber PF, Abdul-Karim FW, Miraldi F. Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: a surgicopathologic study. J Clin Oncol 1999;17:41–5. [24] Chou HH, Chang TC, Yen TC, Ng KK, Hsueh S, Ma SY, et al. Low value of 18F-Fluoro-2-Doexy-D-Glucose Positron Emission Tomography in primary staging of early stage cervical cancer before radical hysterectomy. J Clin Oncol 2006;24:123–8. [25] Hacker NF, Wain GV, Nicklin JL. Resection of bulky positive lymph nodes in patients with cervical carcinoma. Int J Gynecol Cancer 1995;5:250–6. [26] Rotman M, Pajak TF, Choi K, Clery M, Marcial V, Grigsby PW, et al. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. J Am Med Assoc 1995;274:387–93. [27] Grisby PW, Heydon K, Mutch DG, Kim RY, Eifel P. Long-term follow-up o RTOG 92-10: cervical cancer with positive para-aortic lymph nodes. Int J Radiat Oncol Biol Phys 2001;51:982–7. [28] Eifel PJ, Winter K, Morris M, Levemback C, Grisby PW, Cooper J, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and paraaortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 2004;22:872–80. [29] Cosin JA, Fowler JM, Chen MD, Paley PJ, Carson LF, Twiggs LB. Pretreatment surgical staging of patients with cervical carcinoma: the case for lymph node debulking. Cancer 1998;82:2241–8. [30] Kupets R, Thomas GM, Covens A. Is there a role for pelvic lymph node debulking in advanced cervical cancer? Gynecol Oncol 2002;87:163–70. [31] Morice P, Castaigne D. New approaches in “conventional” surgery of uterine cervix cancer. Cancer Radiother 2000;4:122–6.