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Prospective evaluation of surgical staging of advanced cervical cancer via a laparoscopic extraperitoneal approach
Available online at www.sciencedirect.com R
Gynecologic Oncology 91 (2003) 326 –331
www.elsevier.com/locate/ygyno
Prospective evaluation of surgical staging of advanced cervical cancer via a laparoscopic extraperitoneal approach Y. Sonoda, E. Leblanc, D. Querleu,* B. Castelain, T.H. Papageorgiou, E. Lambaudie, and F. Narducci Centre Oscar Lambret, Lille, France Received 18 December 2003
Abstract Purpose. To report on a large series of cervical cancer patients at risk for lymph node metastasis who underwent surgical staging by a novel technique. Methods. Between 1/97 and 3/02, we identified 111 patients who underwent an infrarenal aortic and common iliac lymph node dissection via a laparoscopic extraperitoneal approach for either bulky or locally advanced cervical cancer. We reviewed the medical records and extracted pertinent information. Results. There were no intraoperative complications. Mean patient age was 46 (⫾ 9) years. Mean node count was 19 (⫾ 12). Thirty (27%) patients had lymph node metastasis. The mean operative time was 157 (⫾ 46) min, and mean postoperative stay was 2 days. The majority of complications in the early part of the series were symptomatic lymphoceles. Since 4/01, preventive peritoneal marsupialization has been performed without lymphocele occurrence (37 patients). Two patients (2%) required reoperation. In the node-positive group, extended-field radiation and chemotherapy were well tolerated, but prognosis was dismal (median survival, 27 months). In the node-negative group, the median survival after pelvic radiation limited to the lower level of the surgical dissection was not reached after an average follow-up of 16.6 months. Conclusions. This novel technique is feasible and combines the benefits of laparoscopy with those of a retroperitoneal approach. It can be used to tailor external radiation therapy. The benefits of extended-field radiation therapy remain unclear; however, this approach does not preclude later use of radiation therapy, whereas possibly minimizing associated toxicities secondary to adhesions. © 2003 Elsevier Inc. All rights reserved.
Introduction Invasive cervical cancer spreads primarily by lymphatic dissemination in a predictable pattern. Lymphatic metastases occur first in the pelvic lymph nodes and subsequently spread to the paraaortic region. The incidence of paraaortic tumor spread increases with stage of disease and tumor volume. Prior studies have demonstrated that the incidence of paraaortic lymph node metastasis increases with clinical stage and may be as high as 38% in patients with locally advanced disease [1]. Detection of metastases remains a
* Corresponding author. Department of Surgery, Institut Claudius Regaud, 20 rue duPont Saint Pierre 31052 Toulouse, France. E-mail address: [email protected] 0090-8258/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2003.07.008
problem. These often go undetected because the imaging techniques utilized in conjunction with clinical staging are unable to reliably identify occult lymphatic spread. Surgical sampling remains the gold standard for the detection of occult nodal metastasis, and some have employed pretreatment surgical staging via laparotomy in the management of clinically advanced-stage disease. Although paraaortic metastases confer a worse prognosis, a certain percentage of these patients can be salvaged with extended-field radiation therapy [2] and possibly with the combination of radiation therapy and chemotherapy [3]. In certain settings, surgical staging can spare node-negative patients the need for extended-field radiation, thus reducing the 4% additional grades 3– 4 complication rate associated with paraaortic radiation [2,4]. Because the benefits of surgical staging remain contro-
Y. Sonoda et al. / Gynecologic Oncology 91 (2003) 326 –331
versial and may be of only prognostic benefit, every attempt should be made to minimize the associated morbidity. Surgical staging via laparotomy, even using the extraperitoneal approach, is associated with morbidity and with questionable benefits and therefore is not universally used. Laparoscopy can provide a pathologic sample of radiologically negative nodes without the associated morbidity of a large incision. Additionally, an extraperitoneal approach to the paraaortic node dissection has been associated with less radiation-associated gastrointestinal morbidity [5]. We report on our institution’s experience with a laparoscopic extraperitoneal approach used to surgically stage patients with locally advanced cervical cancer. This approach theoretically combines the benefits of laparoscopy and the extraperitoneal approach. A fraction of these patients have been reported on in a collaborative pilot study [6], yet this remains the largest single series to date employing this new technique for primary surgical staging of advanced cervical cancer in a single institution.
Materials and methods Patient population The study population consisted of patients with pathologically proven cervical cancer who underwent a laparoscopic extraperitoneal paraaortic and common iliac lymph node dissection between January 1997 and March 2002. Patients with clinical Stage IB2-IVA neoplasms according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria were eligible for this procedure. Patients had no radiographic enlarged or cytologically positive paraaortic nodes. According to institutional protocol, these patients undergo diagnostic laparoscopy of the peritoneal cavity to rule out intraabdominal disease. If this is negative, a laparoscopic extraperitoneal dissection is then performed. Medical records were reviewed for patient age, body mass index (BMI), history of prior abdominal surgery, tumor stage, histology, surgical procedure, peri- and postoperative complications, operative time for the extraperitoneal procedure, postoperative stay, lymph node count, and node status. Patient follow-up was obtained from outpatient records. Additional forms of adjuvant treatment and specific radiation-induced gastrointestinal toxicities were noted.
327
Table 1 Patient characteristics Patients (N) Mean patient age (years) Mean Body Mass Index Tumor histology Epidermoid Adenocarcinoma Clear cell Adenosquamous Undifferentiated Prior abdominal surgery Mean operative time Postoperative stay Mean lymph node count
111 46 (⫾ 9) 24 (⫾ 5 kg/m2) 103 5 1 1 1 43 157 (⫾ 46) min 2 days 19 (⫾ 12)
lymphoceles: marsupialization of the peritoneum in the left paracolic gutter is now routinely performed at the end of the procedure. The peritoneum is opened under extraperitoneal or laparoscopic guidance, and a wide communication is made between the extraperitoneal space and peritoneal cavity. Pelvic radiation therapy consisted of a 50-Gy external beam. External pelvic radiation therapy was given through four orthogonal fields. The upper limit of the field was defined using the line of surgical clips delineating the inferior limit of the surgical dissection. The pelvic field extended distally to the midportion of the obturator foramen or lowest level of disease with a 3-cm margin and laterally 2 cm beyond the lateral margins of the bony pelvic wall. The lateral fields extended from the anterior border of the pubic symphysis to encompass S3. Radiation was delivered 5 days a week, 1.8 Gy/session. In patients with positive aortic nodes, 45-Gy extended-field radiation was delivered up to the level of T12–L1. Lateral limits were 4 cm from the midline. Common iliac metastasis was managed the same way as aortic metastasis. In cases that received concurrent chemotherapy, weekly cisplatin was given at a dose of 40 mg/m2. Brachytherapy was then delivered using a 60-Gy isodose surface as described by the International Commission on Radiological Units and Measurements (ICRU) system [7]. Kaplan Meier survival curves were generated using SPSS statistical software (SPSS, Inc., Chicago, IL). The log-rank test was used to evaluate survival differences.
Technique
Results
The dissection template extends from the bifurcation of the iliac arteries to the level of the left renal vein. Surgical clips are routinely used to demarcate the lower limits of the dissection for the radiation oncologist. The details of the procedure have been previously described [6]. One modification has been adopted and used in 37 patients since April 2001 in an attempt to reduce the number of postoperative
We identified 111 patients who met the eligibility criteria. All patients underwent the staging procedure without intraoperative complication necessitating conversion to laparotomy. The clinical characteristics of the patients are listed in Table 1. The mean patient age was 46 (⫾ 9) years old. The mean BMI was 24 (⫾ 5) kg/m2. Clinical FIGO stages of the population were as follows: Stage IB2, 29
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Table 2 Paraaortic node status according to FIGO stage FIGO stage
Total no. of patients
Node-positive patients
% node positive
IB2 IIA IIB IIIA IIIB IVA All
29 5 29 5 42 1 111
9 1 5 1 13 1 30
31 20 17 20 31 100 27
patients; Stage IIA, 5 patients; Stage IIB, 29 patients; Stage IIIA, 5 patients; Stage IIIB, 42 patients; and Stage IVA, 1 patient. Tumor histology was 103 (93%) epidermoid, five adenocarcinoma, one clear cell, one adenosquamous, and one undifferentiated. Information regarding prior abdominal surgery was available for 102 patients. Forty-three (42%) had a history of a prior abdominal procedure; however, 24 (24%) of these were appendectomies. The operative time for the laparoscopic extraperitoneal procedure was available for 93 patients, and the mean was 157 (⫾ 46) min. The mean lymph node count was 19 (⫾ 12). The mean postoperative stay was 2 days. There were 30 (27%) patients who were confirmed to have lymph node metastasis. The estimated blood loss for the majority of cases was under 100 ml. There were no blood transfusions. The distribution by stage is illustrated in Table 2. Despite negative preoperative CT scan or MRI, 27 patients were found to have an enlarged node. Sixteen of these were removed laparoscopically and found to be negative for metastasis by frozen section. In these cases, the dissection was completed. Three patients were found to have a positive enlarged node at the end of the dissection. Five patients had the enlarged node removed laparoscopically, which was found to be positive on frozen section, and the remaining normal-appearing nodes were left in place. Two patients had positive nodes that were felt to be unresectable; thus, they were laparoscopically marked with clips. One patient had a positive node that was ultimately debulked by an extraperitoneal laparotomy. Postoperative complications directly attributable to the procedure were identified in 14 (13%) patients (Table 3). Eleven of the 74 early patients of the series had symptomatic lymphoceles. Eight of these were drained under radiological guidance, two required a drainage catheter placed under general anesthesia, and one required drainage by laparoscopy. There were two retroperitoneal hematomas, of which one required ureteral stent placement. One patient required reoperation for a bowel obstruction resulting from a trocar-site hernia. Thus, five (5%) patients required a second procedure under anesthesia, but only two (2%) required reoperation. These two patients had their radiation delayed secondary to these operative complications. Because the introduction of marsupialization and closure of the
fascia at the level of the umbilical port, no complication or reoperation occurred in the 37 last patients of the series. The complication/reoperation rate is thus expected to be minimal (97.5% confidence interval of 0 of 37 patients is 0 –9%). One patient had a persistent lymphocele, which resulted in a delay of her treatment. The median interval from surgery to radiation was 3.2 weeks (range ⫽ 12); however, this was due in large part to scheduling difficulties after surgery. Twenty-one patients received extended-field radiation chemotherapy and concomitant chemotherapy. Nine patients received extended-field radiation therapy alone. With a mean follow-up of 17 months, there was one case of radiation-induced small-bowel enteritis noted in the patient who was reoperated on for an umbilical port hernia prior to extended-field radiation. Isolated recurrence in the paraaortic region was only noted in one patient who received only extended-field radiation therapy without concomitant chemotherapy. There have been no isolated port-site recurrences noted to date. With an average follow-up of 16.5 months, the overall survival was significantly better in the node-negative group (P ⫽ 0.008) (Fig. 1). Mean survival for the node-negative group was 38.6 months compared to 26.5 months in the node-positive group. Median survival for the node-positive group was 27 months. Six (20%) of 30 node-positive patients developed distant metastasis, whereas 5 (6%) of 81 node-negative patients had distant failure (P ⬍ .05).
Discussion Cervical cancer remains the only major gynecological malignancy to be clinically staged. This is due in large part to the lack of uniformly available technology in the areas where this disease is most prevalent (i.e., third-world countries), where it remains the primary cancer killer in women. However, there exists a large discrepancy between clinical and surgical staging [8]. The majority of these errors are due to the underdiagnosis of lymph node metastasis. Identification of node-positive patients allows therapy to be tailored and provides prognostic information, and although this finding is associated with a poor outcome, a
Table 3 Summary of complications Complication
Number
Symptomatic lymphocele—total no. Radiologic drainage Catheter placement under anesthesia Laparoscopic drainage Retroperitoneal hematoma Bowel obstruction (trocar-site hernia) Required second procedure under anesthesia Required reoperation Total number
11 8 2 1 2 1 5 2 14 (13%)
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Fig. 1. Overall survival in months of node-negative versus node-positive patients (P ⫽ 0.008).
portion of these patients can be saved. The arguments against surgical staging are the associated complications and the amount of benefit gained. Petereit et al. [9] estimated that only 6.8 of 100 patients with locally advanced disease would be saved with surgical staging. These authors reasoned that patients with the highest incidence of paraaortic lymph node metastasis are the least likely to benefit, given the high rates of pelvic and distant failure. The improvement in locoregional failure rates with the combination of radiation and concurrent chemotherapy may justify readdressing this argument. Although the benefits from chemoradiation were noted in patients with locally advanced cervical cancer without paraaortic spread, extendedfield radiation therapy with concurrent chemotherapy is feasible and can achieve control in a portion of patients where disease has spread to the paraaortic nodes [2]. Identification of these patients remains a challenge, however, as the available radiological modalities have been shown to be inaccurate. Given the poor prognosis of patients who are at greatest risk for paraaortic metastasis, can the added morbidity and mortality of this procedure be justified? This remains the
subject of debate. It has been well documented that nonsurgical methods of evaluating the paraaortic lymph nodes are inaccurate. In a large Gynecologic Oncology Group (GOG) trial evaluating diagnostic modalities for detecting paraaortic node spread, CT scan and ultrasound had a sensitivity of only 34 and 19%, respectively [10]. Goff et al. [11] also reported a sensitivity of 35% in detecting nodal disease in their series. Lymphangiogram had the highest sensitivity at 79%, but lymphangiogram is not readily available. MRI and PET scan also have been studied as potential methods of identifying paraaortic disease. MRI has been shown to have a sensitivity of only 57% in detecting paraaortic metastasis in cervical cancer. Rose et al. [12] found that six of eight patients (75%) with positive paraaortic nodes had evidence of metastasis on PET scan. However, like lymphangiogram, PET scanners are not readily available. Without question, surgical sampling remains the gold standard to evaluate lymph node status. However, surgical staging subjects the patient to the morbidity of the procedure and the possible subsequent toxicities associated with the combination of surgery and radiation. Traditional laparotomy has been associated with increased enteric compli-
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cations, presumably secondary to intraabdominal adhesion formation. Employing an extraperitoneal approach rather than a transperitoneal one can decrease these complications [13], but this approach still subjects the patient to the morbidity associated with a large incision. The growing use of laparoscopic surgery in the management of gynecologic malignancies has become evident in the management of cervical cancer. Dargent [14] pioneered laparoscopic removal of lymph nodes in 1987. A major advantage of its use is its association with shortened hospital stay [15]. Patients from our series had a mean postoperative hospitalization of 2 days, but the majority of these patients are ready to leave the hospital on the first postoperative day. Additional benefits of this laparoscopic approach are evident in the complication rate. Nelson et al. [1] reported that 15 (14%) of 104 patients with locally advanced cervical cancer who underwent the surgical staging procedure by laparotomy had wound complications, including 5 wound dehiscences and 5 eviscerations. Similarly, Holcomb et al. [16] reported 6 (6.7%) of 89 patients who underwent surgical staging by laparotomy and had major wound complications, including 5 fascial dehiscences and 1 evisceration. In our series, we had a total of 14 (13%) postoperative complications directly related to the procedure; however, only one was a major wound complication. This case was an incarcerated hernia at an umbilical trocar site that required reoperation and small-bowel resection. In retrospect, the fascia at this trocar site had not been closed at the conclusion of the staging laparoscopy. Since this incident, the fascia at all port sites 10 ml or greater are closed, and there have been no additional hernias. The laparoscopic approach can nearly eliminate major postoperative wound complications. Ten symptomatic lymphoceles comprised the majority of the postoperative complications. Since concluding the procedure with the marsupialization, we have experienced not symptomatic postoperative lymphoceles to date (N ⫽ 37 patients). Querleu et al. [17] were the first to employ a laparoscopic transperitoneal lymphadenectomy in the management of patients with cervical cancer. This technique minimizes intraabdominal adhesion formation in a porcine model [18,19]. The combination of laparoscopy with an extraperitoneal approach in the staging of cervical cancer has been described [6,20,21]. Such an approach combines the benefits of an extraperitoneal approach with those of minimally invasive surgery. Additionally, in an experimental controlled study, Occelli et al. [22] demonstrated the decreased formation of adhesions after the laparoscopic extraperitoneal approach when compared to the transperitoneal laparoscopic approach. Interestingly, the majority of adhesions formed after the extraperitoneal approach was located outside the paraaortic external radiation field. Intraabdominal adhesion formation is a major causative factor for radiationinduced small-bowel injury after surgical staging. In our series, there was only one recorded case of small-bowel
enteritis after radiation. This occurred in the patient who underwent a small-bowel resection prior to radiation therapy for an incarcerated umbilical trocar-site hernia after staging laparoscopy. An intraoperative advantage to this approach is that prior abdominal surgery with associated adhesions does not seem to impact on the success of the operation. Forty-three patients in our series had a history of a prior abdominal procedure. Although the majority of these were appendectomies, the extraperitoneal dissection was completed in all patients. Other theoretical advantages include the decreased risk of electrosurgical bowel injury or enterotomy, as the bowel is elevated out of the operative field by the peritoneal envelope. Laparoscopic lymph node dissection has been shown to be comparable to laparotomy in terms of node counts [15,18]. Prior studies comparing the laparoscopic technique to laparotomy have focused on the laparoscopic transperitoneal approach. The node count from a left-sided laparoscopic extraperitoneal approach has been shown to be comparable to that of a transperitoneal approach [22]. Additionally, Dargent et al. [23] compared the left-sided approach to the bilateral extraperitoneal approach. The overall node counts in his series were similar, but the right-sided node count was lower using the left-sided extraperitoneal approach. He reasoned that because the left-sided paraaortic nodes are more often involved [24], this should be the side more thoroughly sampled. Given that this is a diagnostic procedure, we are in agreement with his conclusion. In our series, the mean number of nodes obtained by the left-sided laparoscopic extraperitoneal approach was 19. This number included patients with grossly involved nodes who had a selective lymph node removal. It is also comparable to other series evaluating paraaortic lymphadenectomy by an open extraperitoneal approach [25]. In general, patients in France with FIGO stage IB2 cervical cancers are routinely treated with pelvic radiation plus concomitant chemotherapy. Patients with higher stage tumors are in some centers given prophylactic extended-field radiation therapy with chemotherapy. Following this algorithm, excluding the patients with recurrent disease, 9 (31%) of 29 patients with stage IB2 tumors would have been undertreated and 61 (74%) of 82 with stage IIA–IVA tumors would have been overtreated. The administration of extended-field radiation is not without risk, as the addition of the extended field may significantly increase the incidence of gastrointestinal complications [4]. As in our study, others have also reported treatment modifications in a high percentage of surgically staged patients [11]. The usefulness of surgically staging in tailoring therapy for these patients is thus demonstrated. Paraaortic nodal metastasis is a poor-prognosis factor. Median survival similar to ours has been reported in larger series of paraaortic node-positive patients treated with extended-field radiation with concomitant chemotherapy [3]. The higher percentage of distant recurrences may be a clue
Y. Sonoda et al. / Gynecologic Oncology 91 (2003) 326 –331
as to why overall survival is still low. Paraaortic node metastasis may be a harbinger for systemic spread; thus, we must continue to search for more effective means of systemic therapy. Despite this, a certain percentage of patients with paraaortic metastasis will be cured if identified. In conclusion, laparoscopic extraperitoneal aortic and common iliac lymph node dissection is a feasible technique that combines the benefits of laparoscopy with those of a retroperitoneal approach. As histological diagnosis is the gold standard for determining lymph node status, this novel approach provides a means of surgically evaluating patients for subclinical metastasis who may benefit from extendedfield radiation therapy and to determine eligibility for new clinical trials that may require pathologic documentation of negative paraaortic nodes. In addition, this approach seems to minimize many of the risks traditionally associated with surgical staging via laparotomy. This must be kept in mind, as the long-term survival benefits of surgical staging have yet to be proven. References [1] Nelson JH Jr, Boyce J, Macasaet M, Lu T, Bohorquez JF, Nicastri AD, Fruchter R. Incidence, significance, and follow-up of para-aortic lymph node metastases in late invasive carcinoma of the cervix. Am J Obstet Gynecol 1977;128:336 – 40. [2] Rotman M, Pajak TF, Choi K, Clery M, Marcial V, Grigsby PW, Cooper J, John M. Prophylactic extended-field irradiation of paraaortic 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. [3] Varia MA, Bundy BN, Deppe G, Mannel R, Averette HE, Rose PG, Connelly P. Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 1998;42:1015–23. [4] Haie C, Pejovic MH, Gerbaulet A, Horiot JC, Pourquier H, Delouche J, Heinz JF, Brune D, Fenton J, Pizzi G, et al. Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiation therapy group. Radiother Oncol 1988;11(2):101–12. [5] Berman ML, Lagasse LD, Watring WG, Ballon SC, Schlesinger RE, Moore JG, Donaldson RC. The operative evaluation of patients with cervical carcinoma by an extraperitoneal approach. Obstet Gynecol 1977;50(6):658 – 64. [6] Querleu D, Dargent D, Ansquer Y, Leblanc E, Narducci F. Extraperitoneal endosurgical aortic and common iliac dissection in the staging of bulky or advanced cervical carcinomas. Cancer 2000;88: 1883–91. [7] ICRU Report 38. Dose and volume specifications for reporting intracavitary therapy in gynecology. Bethesda: International Commission on Radiological Units and Measurements, 1985. [8] Averette HE, Dudan RC, Ford JH Jr. Exploratory celiotomy for surgical staging of cervical cancer. Am J Obstet Gynecol 1972;113: 1090 – 6.
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[9] Petereit DG, Hartenbach EM, Thomas GM. Para-aortic lymph node evaluation in cervical cancer: the impact of staging upon treatment decisions and outcome. Int J Gynecol Oncol 1998;69:243–7. [10] Heller PB, Maletano JH, Bundy BN, Barnhill DR, Okagaki T. Clinical-pathologic study of stage IIB, III, and IVA carcinoma of the cervix: extended diagnostic evaluation for paraaortic node metastasis—a Gynecologic Oncology Group study. Gynecol Oncol 1990;38: 425–30. [11] Goff BA, Muntz HG, Paley PJ, Tamimi HK, Koh WJ, Greer BE. Impact of surgical staging in women with locally advanced cervical cancer. Gynecol Oncol 1999;74:436 – 42. [12] 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. [13] Fine BA, Hempling RE, Piver MS, Baker TR, McAuley M, Driscoll D. Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. Int J Radiat Oncol Biol Phys 1995;31:717–23. [14] Dargent D. New future for Schauta’s operation through pre-surgical retroperitoneal pelviscopy. Eur J Gynecol Oncol 1987;8:292– 6. [15] Scribner DR Jr, Walker JL, Johnson GA, McMeekin SD, Gold MA, Mannel RS. Laparoscopic pelvic and paraaortic lymph node dissection: analysis of the first 100 cases. Gynecol Oncol 2001;82:498 –503. [16] Holcomb K, Abulafia O, Matthews RP, Gabbur N, Lee YC, Buhl A. The impact of pretreatment staging laparotomy on survival in locally advanced cervical carcinoma. Eur J Gynaecol Oncol 1999;20:90 –3. [17] 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. [18] Lanvin D, Elhage A, Henry B, Leblanc E, Querleu D, DelobelleDeroide A. Accuracy and safety of laparoscopic lymphadenectomy: an experimental prospective randomized study. Gynecol Oncol 1997; 67:83–7. [19] Chen MD, Teigen GA, Reynolds HT, Johnson PR, Fowler JM. Laparoscopy versus laparotomy: an evaluation of adhesion formation after pelvic and paraaortic lymphadenectomy in a porcine model. Am J Obstet Gynecol 1998;178:499 –503. [20] Vasilev SA, McGonigle KF. Extraperitoneal laparoscopic para-aortic lymph node dissection. Gynecol Oncol 1996;61:315–20. [21] Dargent D. Extraperitoneal aortic dissection. Award video presented at the Meeting of the Society of Gynecologic Oncologists, Phoenix, AZ, 1997. [22] Occelli B, Narducci F, Lanvin D, Querleu D, Coste E, Castelain B, Gibon D, LeBlanc E. De novo adhesions with extraperitoneal endosurgical para-aortic lymphadenectomy versus transperitoneal laparoscopic para-aortic lymphadenectomy: a randomized experimental study. Am J Obstet Gynecol 2000;183:529 –33. [23] Dargent D, Ansquer Y, Mathevet P. Technical development and results of left extraperitoneal laparoscopic paraaortic lymphadenectomy for cervical cancer. Gynecol Oncol 2000;77:87–92. [24] Michel G, Morice P, Castaigne D, Leblanc M, Rey A, Duvillard P. Lymphatic spread in stage Ib and II cervical carcinoma: anatomy and surgical implications. Obstet Gynecol 1998;91:360 –3. [25] Gallup DG, King LA, Messing MJ, Talledo OE. Paraaortic lymph node sampling by means of an extraperitoneal approach with a supraumbilical transverse “sunrise” incision. Am J Obstet Gynecol 1993;169:307–11.
Gynecologic Oncology 91 (2003) 326 –331
www.elsevier.com/locate/ygyno
Prospective evaluation of surgical staging of advanced cervical cancer via a laparoscopic extraperitoneal approach Y. Sonoda, E. Leblanc, D. Querleu,* B. Castelain, T.H. Papageorgiou, E. Lambaudie, and F. Narducci Centre Oscar Lambret, Lille, France Received 18 December 2003
Abstract Purpose. To report on a large series of cervical cancer patients at risk for lymph node metastasis who underwent surgical staging by a novel technique. Methods. Between 1/97 and 3/02, we identified 111 patients who underwent an infrarenal aortic and common iliac lymph node dissection via a laparoscopic extraperitoneal approach for either bulky or locally advanced cervical cancer. We reviewed the medical records and extracted pertinent information. Results. There were no intraoperative complications. Mean patient age was 46 (⫾ 9) years. Mean node count was 19 (⫾ 12). Thirty (27%) patients had lymph node metastasis. The mean operative time was 157 (⫾ 46) min, and mean postoperative stay was 2 days. The majority of complications in the early part of the series were symptomatic lymphoceles. Since 4/01, preventive peritoneal marsupialization has been performed without lymphocele occurrence (37 patients). Two patients (2%) required reoperation. In the node-positive group, extended-field radiation and chemotherapy were well tolerated, but prognosis was dismal (median survival, 27 months). In the node-negative group, the median survival after pelvic radiation limited to the lower level of the surgical dissection was not reached after an average follow-up of 16.6 months. Conclusions. This novel technique is feasible and combines the benefits of laparoscopy with those of a retroperitoneal approach. It can be used to tailor external radiation therapy. The benefits of extended-field radiation therapy remain unclear; however, this approach does not preclude later use of radiation therapy, whereas possibly minimizing associated toxicities secondary to adhesions. © 2003 Elsevier Inc. All rights reserved.
Introduction Invasive cervical cancer spreads primarily by lymphatic dissemination in a predictable pattern. Lymphatic metastases occur first in the pelvic lymph nodes and subsequently spread to the paraaortic region. The incidence of paraaortic tumor spread increases with stage of disease and tumor volume. Prior studies have demonstrated that the incidence of paraaortic lymph node metastasis increases with clinical stage and may be as high as 38% in patients with locally advanced disease [1]. Detection of metastases remains a
* Corresponding author. Department of Surgery, Institut Claudius Regaud, 20 rue duPont Saint Pierre 31052 Toulouse, France. E-mail address: [email protected] 0090-8258/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2003.07.008
problem. These often go undetected because the imaging techniques utilized in conjunction with clinical staging are unable to reliably identify occult lymphatic spread. Surgical sampling remains the gold standard for the detection of occult nodal metastasis, and some have employed pretreatment surgical staging via laparotomy in the management of clinically advanced-stage disease. Although paraaortic metastases confer a worse prognosis, a certain percentage of these patients can be salvaged with extended-field radiation therapy [2] and possibly with the combination of radiation therapy and chemotherapy [3]. In certain settings, surgical staging can spare node-negative patients the need for extended-field radiation, thus reducing the 4% additional grades 3– 4 complication rate associated with paraaortic radiation [2,4]. Because the benefits of surgical staging remain contro-
Y. Sonoda et al. / Gynecologic Oncology 91 (2003) 326 –331
versial and may be of only prognostic benefit, every attempt should be made to minimize the associated morbidity. Surgical staging via laparotomy, even using the extraperitoneal approach, is associated with morbidity and with questionable benefits and therefore is not universally used. Laparoscopy can provide a pathologic sample of radiologically negative nodes without the associated morbidity of a large incision. Additionally, an extraperitoneal approach to the paraaortic node dissection has been associated with less radiation-associated gastrointestinal morbidity [5]. We report on our institution’s experience with a laparoscopic extraperitoneal approach used to surgically stage patients with locally advanced cervical cancer. This approach theoretically combines the benefits of laparoscopy and the extraperitoneal approach. A fraction of these patients have been reported on in a collaborative pilot study [6], yet this remains the largest single series to date employing this new technique for primary surgical staging of advanced cervical cancer in a single institution.
Materials and methods Patient population The study population consisted of patients with pathologically proven cervical cancer who underwent a laparoscopic extraperitoneal paraaortic and common iliac lymph node dissection between January 1997 and March 2002. Patients with clinical Stage IB2-IVA neoplasms according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria were eligible for this procedure. Patients had no radiographic enlarged or cytologically positive paraaortic nodes. According to institutional protocol, these patients undergo diagnostic laparoscopy of the peritoneal cavity to rule out intraabdominal disease. If this is negative, a laparoscopic extraperitoneal dissection is then performed. Medical records were reviewed for patient age, body mass index (BMI), history of prior abdominal surgery, tumor stage, histology, surgical procedure, peri- and postoperative complications, operative time for the extraperitoneal procedure, postoperative stay, lymph node count, and node status. Patient follow-up was obtained from outpatient records. Additional forms of adjuvant treatment and specific radiation-induced gastrointestinal toxicities were noted.
327
Table 1 Patient characteristics Patients (N) Mean patient age (years) Mean Body Mass Index Tumor histology Epidermoid Adenocarcinoma Clear cell Adenosquamous Undifferentiated Prior abdominal surgery Mean operative time Postoperative stay Mean lymph node count
111 46 (⫾ 9) 24 (⫾ 5 kg/m2) 103 5 1 1 1 43 157 (⫾ 46) min 2 days 19 (⫾ 12)
lymphoceles: marsupialization of the peritoneum in the left paracolic gutter is now routinely performed at the end of the procedure. The peritoneum is opened under extraperitoneal or laparoscopic guidance, and a wide communication is made between the extraperitoneal space and peritoneal cavity. Pelvic radiation therapy consisted of a 50-Gy external beam. External pelvic radiation therapy was given through four orthogonal fields. The upper limit of the field was defined using the line of surgical clips delineating the inferior limit of the surgical dissection. The pelvic field extended distally to the midportion of the obturator foramen or lowest level of disease with a 3-cm margin and laterally 2 cm beyond the lateral margins of the bony pelvic wall. The lateral fields extended from the anterior border of the pubic symphysis to encompass S3. Radiation was delivered 5 days a week, 1.8 Gy/session. In patients with positive aortic nodes, 45-Gy extended-field radiation was delivered up to the level of T12–L1. Lateral limits were 4 cm from the midline. Common iliac metastasis was managed the same way as aortic metastasis. In cases that received concurrent chemotherapy, weekly cisplatin was given at a dose of 40 mg/m2. Brachytherapy was then delivered using a 60-Gy isodose surface as described by the International Commission on Radiological Units and Measurements (ICRU) system [7]. Kaplan Meier survival curves were generated using SPSS statistical software (SPSS, Inc., Chicago, IL). The log-rank test was used to evaluate survival differences.
Technique
Results
The dissection template extends from the bifurcation of the iliac arteries to the level of the left renal vein. Surgical clips are routinely used to demarcate the lower limits of the dissection for the radiation oncologist. The details of the procedure have been previously described [6]. One modification has been adopted and used in 37 patients since April 2001 in an attempt to reduce the number of postoperative
We identified 111 patients who met the eligibility criteria. All patients underwent the staging procedure without intraoperative complication necessitating conversion to laparotomy. The clinical characteristics of the patients are listed in Table 1. The mean patient age was 46 (⫾ 9) years old. The mean BMI was 24 (⫾ 5) kg/m2. Clinical FIGO stages of the population were as follows: Stage IB2, 29
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Table 2 Paraaortic node status according to FIGO stage FIGO stage
Total no. of patients
Node-positive patients
% node positive
IB2 IIA IIB IIIA IIIB IVA All
29 5 29 5 42 1 111
9 1 5 1 13 1 30
31 20 17 20 31 100 27
patients; Stage IIA, 5 patients; Stage IIB, 29 patients; Stage IIIA, 5 patients; Stage IIIB, 42 patients; and Stage IVA, 1 patient. Tumor histology was 103 (93%) epidermoid, five adenocarcinoma, one clear cell, one adenosquamous, and one undifferentiated. Information regarding prior abdominal surgery was available for 102 patients. Forty-three (42%) had a history of a prior abdominal procedure; however, 24 (24%) of these were appendectomies. The operative time for the laparoscopic extraperitoneal procedure was available for 93 patients, and the mean was 157 (⫾ 46) min. The mean lymph node count was 19 (⫾ 12). The mean postoperative stay was 2 days. There were 30 (27%) patients who were confirmed to have lymph node metastasis. The estimated blood loss for the majority of cases was under 100 ml. There were no blood transfusions. The distribution by stage is illustrated in Table 2. Despite negative preoperative CT scan or MRI, 27 patients were found to have an enlarged node. Sixteen of these were removed laparoscopically and found to be negative for metastasis by frozen section. In these cases, the dissection was completed. Three patients were found to have a positive enlarged node at the end of the dissection. Five patients had the enlarged node removed laparoscopically, which was found to be positive on frozen section, and the remaining normal-appearing nodes were left in place. Two patients had positive nodes that were felt to be unresectable; thus, they were laparoscopically marked with clips. One patient had a positive node that was ultimately debulked by an extraperitoneal laparotomy. Postoperative complications directly attributable to the procedure were identified in 14 (13%) patients (Table 3). Eleven of the 74 early patients of the series had symptomatic lymphoceles. Eight of these were drained under radiological guidance, two required a drainage catheter placed under general anesthesia, and one required drainage by laparoscopy. There were two retroperitoneal hematomas, of which one required ureteral stent placement. One patient required reoperation for a bowel obstruction resulting from a trocar-site hernia. Thus, five (5%) patients required a second procedure under anesthesia, but only two (2%) required reoperation. These two patients had their radiation delayed secondary to these operative complications. Because the introduction of marsupialization and closure of the
fascia at the level of the umbilical port, no complication or reoperation occurred in the 37 last patients of the series. The complication/reoperation rate is thus expected to be minimal (97.5% confidence interval of 0 of 37 patients is 0 –9%). One patient had a persistent lymphocele, which resulted in a delay of her treatment. The median interval from surgery to radiation was 3.2 weeks (range ⫽ 12); however, this was due in large part to scheduling difficulties after surgery. Twenty-one patients received extended-field radiation chemotherapy and concomitant chemotherapy. Nine patients received extended-field radiation therapy alone. With a mean follow-up of 17 months, there was one case of radiation-induced small-bowel enteritis noted in the patient who was reoperated on for an umbilical port hernia prior to extended-field radiation. Isolated recurrence in the paraaortic region was only noted in one patient who received only extended-field radiation therapy without concomitant chemotherapy. There have been no isolated port-site recurrences noted to date. With an average follow-up of 16.5 months, the overall survival was significantly better in the node-negative group (P ⫽ 0.008) (Fig. 1). Mean survival for the node-negative group was 38.6 months compared to 26.5 months in the node-positive group. Median survival for the node-positive group was 27 months. Six (20%) of 30 node-positive patients developed distant metastasis, whereas 5 (6%) of 81 node-negative patients had distant failure (P ⬍ .05).
Discussion Cervical cancer remains the only major gynecological malignancy to be clinically staged. This is due in large part to the lack of uniformly available technology in the areas where this disease is most prevalent (i.e., third-world countries), where it remains the primary cancer killer in women. However, there exists a large discrepancy between clinical and surgical staging [8]. The majority of these errors are due to the underdiagnosis of lymph node metastasis. Identification of node-positive patients allows therapy to be tailored and provides prognostic information, and although this finding is associated with a poor outcome, a
Table 3 Summary of complications Complication
Number
Symptomatic lymphocele—total no. Radiologic drainage Catheter placement under anesthesia Laparoscopic drainage Retroperitoneal hematoma Bowel obstruction (trocar-site hernia) Required second procedure under anesthesia Required reoperation Total number
11 8 2 1 2 1 5 2 14 (13%)
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Fig. 1. Overall survival in months of node-negative versus node-positive patients (P ⫽ 0.008).
portion of these patients can be saved. The arguments against surgical staging are the associated complications and the amount of benefit gained. Petereit et al. [9] estimated that only 6.8 of 100 patients with locally advanced disease would be saved with surgical staging. These authors reasoned that patients with the highest incidence of paraaortic lymph node metastasis are the least likely to benefit, given the high rates of pelvic and distant failure. The improvement in locoregional failure rates with the combination of radiation and concurrent chemotherapy may justify readdressing this argument. Although the benefits from chemoradiation were noted in patients with locally advanced cervical cancer without paraaortic spread, extendedfield radiation therapy with concurrent chemotherapy is feasible and can achieve control in a portion of patients where disease has spread to the paraaortic nodes [2]. Identification of these patients remains a challenge, however, as the available radiological modalities have been shown to be inaccurate. Given the poor prognosis of patients who are at greatest risk for paraaortic metastasis, can the added morbidity and mortality of this procedure be justified? This remains the
subject of debate. It has been well documented that nonsurgical methods of evaluating the paraaortic lymph nodes are inaccurate. In a large Gynecologic Oncology Group (GOG) trial evaluating diagnostic modalities for detecting paraaortic node spread, CT scan and ultrasound had a sensitivity of only 34 and 19%, respectively [10]. Goff et al. [11] also reported a sensitivity of 35% in detecting nodal disease in their series. Lymphangiogram had the highest sensitivity at 79%, but lymphangiogram is not readily available. MRI and PET scan also have been studied as potential methods of identifying paraaortic disease. MRI has been shown to have a sensitivity of only 57% in detecting paraaortic metastasis in cervical cancer. Rose et al. [12] found that six of eight patients (75%) with positive paraaortic nodes had evidence of metastasis on PET scan. However, like lymphangiogram, PET scanners are not readily available. Without question, surgical sampling remains the gold standard to evaluate lymph node status. However, surgical staging subjects the patient to the morbidity of the procedure and the possible subsequent toxicities associated with the combination of surgery and radiation. Traditional laparotomy has been associated with increased enteric compli-
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cations, presumably secondary to intraabdominal adhesion formation. Employing an extraperitoneal approach rather than a transperitoneal one can decrease these complications [13], but this approach still subjects the patient to the morbidity associated with a large incision. The growing use of laparoscopic surgery in the management of gynecologic malignancies has become evident in the management of cervical cancer. Dargent [14] pioneered laparoscopic removal of lymph nodes in 1987. A major advantage of its use is its association with shortened hospital stay [15]. Patients from our series had a mean postoperative hospitalization of 2 days, but the majority of these patients are ready to leave the hospital on the first postoperative day. Additional benefits of this laparoscopic approach are evident in the complication rate. Nelson et al. [1] reported that 15 (14%) of 104 patients with locally advanced cervical cancer who underwent the surgical staging procedure by laparotomy had wound complications, including 5 wound dehiscences and 5 eviscerations. Similarly, Holcomb et al. [16] reported 6 (6.7%) of 89 patients who underwent surgical staging by laparotomy and had major wound complications, including 5 fascial dehiscences and 1 evisceration. In our series, we had a total of 14 (13%) postoperative complications directly related to the procedure; however, only one was a major wound complication. This case was an incarcerated hernia at an umbilical trocar site that required reoperation and small-bowel resection. In retrospect, the fascia at this trocar site had not been closed at the conclusion of the staging laparoscopy. Since this incident, the fascia at all port sites 10 ml or greater are closed, and there have been no additional hernias. The laparoscopic approach can nearly eliminate major postoperative wound complications. Ten symptomatic lymphoceles comprised the majority of the postoperative complications. Since concluding the procedure with the marsupialization, we have experienced not symptomatic postoperative lymphoceles to date (N ⫽ 37 patients). Querleu et al. [17] were the first to employ a laparoscopic transperitoneal lymphadenectomy in the management of patients with cervical cancer. This technique minimizes intraabdominal adhesion formation in a porcine model [18,19]. The combination of laparoscopy with an extraperitoneal approach in the staging of cervical cancer has been described [6,20,21]. Such an approach combines the benefits of an extraperitoneal approach with those of minimally invasive surgery. Additionally, in an experimental controlled study, Occelli et al. [22] demonstrated the decreased formation of adhesions after the laparoscopic extraperitoneal approach when compared to the transperitoneal laparoscopic approach. Interestingly, the majority of adhesions formed after the extraperitoneal approach was located outside the paraaortic external radiation field. Intraabdominal adhesion formation is a major causative factor for radiationinduced small-bowel injury after surgical staging. In our series, there was only one recorded case of small-bowel
enteritis after radiation. This occurred in the patient who underwent a small-bowel resection prior to radiation therapy for an incarcerated umbilical trocar-site hernia after staging laparoscopy. An intraoperative advantage to this approach is that prior abdominal surgery with associated adhesions does not seem to impact on the success of the operation. Forty-three patients in our series had a history of a prior abdominal procedure. Although the majority of these were appendectomies, the extraperitoneal dissection was completed in all patients. Other theoretical advantages include the decreased risk of electrosurgical bowel injury or enterotomy, as the bowel is elevated out of the operative field by the peritoneal envelope. Laparoscopic lymph node dissection has been shown to be comparable to laparotomy in terms of node counts [15,18]. Prior studies comparing the laparoscopic technique to laparotomy have focused on the laparoscopic transperitoneal approach. The node count from a left-sided laparoscopic extraperitoneal approach has been shown to be comparable to that of a transperitoneal approach [22]. Additionally, Dargent et al. [23] compared the left-sided approach to the bilateral extraperitoneal approach. The overall node counts in his series were similar, but the right-sided node count was lower using the left-sided extraperitoneal approach. He reasoned that because the left-sided paraaortic nodes are more often involved [24], this should be the side more thoroughly sampled. Given that this is a diagnostic procedure, we are in agreement with his conclusion. In our series, the mean number of nodes obtained by the left-sided laparoscopic extraperitoneal approach was 19. This number included patients with grossly involved nodes who had a selective lymph node removal. It is also comparable to other series evaluating paraaortic lymphadenectomy by an open extraperitoneal approach [25]. In general, patients in France with FIGO stage IB2 cervical cancers are routinely treated with pelvic radiation plus concomitant chemotherapy. Patients with higher stage tumors are in some centers given prophylactic extended-field radiation therapy with chemotherapy. Following this algorithm, excluding the patients with recurrent disease, 9 (31%) of 29 patients with stage IB2 tumors would have been undertreated and 61 (74%) of 82 with stage IIA–IVA tumors would have been overtreated. The administration of extended-field radiation is not without risk, as the addition of the extended field may significantly increase the incidence of gastrointestinal complications [4]. As in our study, others have also reported treatment modifications in a high percentage of surgically staged patients [11]. The usefulness of surgically staging in tailoring therapy for these patients is thus demonstrated. Paraaortic nodal metastasis is a poor-prognosis factor. Median survival similar to ours has been reported in larger series of paraaortic node-positive patients treated with extended-field radiation with concomitant chemotherapy [3]. The higher percentage of distant recurrences may be a clue
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as to why overall survival is still low. Paraaortic node metastasis may be a harbinger for systemic spread; thus, we must continue to search for more effective means of systemic therapy. Despite this, a certain percentage of patients with paraaortic metastasis will be cured if identified. In conclusion, laparoscopic extraperitoneal aortic and common iliac lymph node dissection is a feasible technique that combines the benefits of laparoscopy with those of a retroperitoneal approach. As histological diagnosis is the gold standard for determining lymph node status, this novel approach provides a means of surgically evaluating patients for subclinical metastasis who may benefit from extendedfield radiation therapy and to determine eligibility for new clinical trials that may require pathologic documentation of negative paraaortic nodes. In addition, this approach seems to minimize many of the risks traditionally associated with surgical staging via laparotomy. This must be kept in mind, as the long-term survival benefits of surgical staging have yet to be proven. References [1] Nelson JH Jr, Boyce J, Macasaet M, Lu T, Bohorquez JF, Nicastri AD, Fruchter R. Incidence, significance, and follow-up of para-aortic lymph node metastases in late invasive carcinoma of the cervix. Am J Obstet Gynecol 1977;128:336 – 40. [2] Rotman M, Pajak TF, Choi K, Clery M, Marcial V, Grigsby PW, Cooper J, John M. Prophylactic extended-field irradiation of paraaortic 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. [3] Varia MA, Bundy BN, Deppe G, Mannel R, Averette HE, Rose PG, Connelly P. Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 1998;42:1015–23. [4] Haie C, Pejovic MH, Gerbaulet A, Horiot JC, Pourquier H, Delouche J, Heinz JF, Brune D, Fenton J, Pizzi G, et al. Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiation therapy group. Radiother Oncol 1988;11(2):101–12. [5] Berman ML, Lagasse LD, Watring WG, Ballon SC, Schlesinger RE, Moore JG, Donaldson RC. The operative evaluation of patients with cervical carcinoma by an extraperitoneal approach. Obstet Gynecol 1977;50(6):658 – 64. [6] Querleu D, Dargent D, Ansquer Y, Leblanc E, Narducci F. Extraperitoneal endosurgical aortic and common iliac dissection in the staging of bulky or advanced cervical carcinomas. Cancer 2000;88: 1883–91. [7] ICRU Report 38. Dose and volume specifications for reporting intracavitary therapy in gynecology. Bethesda: International Commission on Radiological Units and Measurements, 1985. [8] Averette HE, Dudan RC, Ford JH Jr. Exploratory celiotomy for surgical staging of cervical cancer. Am J Obstet Gynecol 1972;113: 1090 – 6.
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