Smits, Roos Marthe MD; Zusterzeel, Petra L.M. MD, PhD; Bekkers, Ruud L.M. MD, PhD
Cervical cancer is the second most common cancer among women worldwide.1 Although the incidence of cervical cancer in the Netherlands is decreasing because of effective screening, it is still the third most common gynecological malignancy, with 718 new cases reported in 2010.2
International Federation of Gynecology and Obstetrics (FIGO; Fédération Internationale Gynaecologique et Obstétrique) staging for cervical cancer is based on clinical features and forms the basis for the decision to recommend surgery or chemoradiation. Staging becomes increasingly inaccurate as the disease progresses, with failure rates rising from 25% in stage I and II to 65% to 90% in stage IIIB.3 The most important prognostic factor for disease recurrence in cervical cancer together with tumor stage is para-aortic nodal status.4 Positive para-aortic lymph nodes (PALNs) are quite common in patients with pelvic lymph node (PLN) metastases, whereas solitary PALN metastasis in the absence of involved PLN is extremely rare and reported to be less than 1% of PALN metastases.5–7
Para-aortic lymph node metastases are present in 9% to 24% in stage II, 12% to 38% in stage III, and 13% to 50% in stage IVA disease.5,8–10 Failure to detect metastases to these lymph nodes may lead to suboptimal treatment and subsequently to decrease in survival.11
Several imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography–CT (PET-CT) have been used in the preoperative staging process. Although PET-CT seems the most sensitive, its limitation in diagnosing microscopic lymph node spread is specified as metastases up to 5 mm.12 Staging surgery has seemed to be feasible and offers individualized treatment.13 Recent studies have shown that surgical staging of patients with locally advanced cervical cancer may lead to treatment modification in 20% to 40% of the patients, resulting in improved survival.3,14–17 However, more extensive surgery may increase morbidity and delay treatment.18
The aim of this review was to evaluate the safety and impact of pretreatment surgical PALN staging (PALNS) in advanced cervical cancer (FIGO stage IB2-IVA) in relation to preoperative imaging.
An extensive literature search was performed to identify data investigating the role of surgical PALN assessment. Our primary objective was to evaluate the feasibility and safety of pretreatment retroperitoneal laparoscopic or robot-assisted para-aortic lymphadenectomy and its impact on detection of metastases.
Relevant articles were identified in PubMed and the Cochrane Library (every year up to January 2014) using the key words or MeSH terms cervical cancer, surgical staging, para-aortic lymph node metastases, para-aortic lymphadenectomy, lymphadenectomy, laparoscopy, robot or robot-assisted, and imaging. All selected articles were scanned for relevant references or “related articles” (PubMed). Selection criteria included English-language and advanced-stage cervical cancer articles (FIGO stage IB2-IVA).
A total of 70 articles were identified using the terms cervical cancer, para-aortic lymph node metastases, and surgical staging or imaging, of which 61 were in English. Most of these articles were not related to the study question. Only a limited number of articles focused on surgical para-aortic lymphadenectomy. Eventually, 22 articles were selected directly, through references or related article search (Fig. 1). The main reasons for excluding studies were as follows: not written in the English language, cervical cancer cases included were not in the advanced stage, insufficient data, and histopathology was not used as standard criterion for lymph node evaluation.
Table 1 presents the collected data from all 22 studies.8,14,17,19–37 Fifteen studies (68%) were designed as a prospective trial; 6 studies (27%), as a retrospective trial; and 1 study (5%), as a randomized controlled trial. Computed tomography, MRI, and PET/PET-CT, used to identify PALN metastases, show a wide variety in positive predictive value (PPV) and negative predictive value (NPV). The proportions of para-aortic nodes that were positive on histological analysis when findings on imaging were abnormal were 20% to 66% for CT scan, 0% to 27% for MRI, 86% to 100% for PET, and 50% to 75% for PET-CT scan. The NPVs of CT, MRI, PET, and PET-CT were 53% to 92%, 75% to 91%, 87% to 94%, and 83% to 92%, respectively. Positive PALNs with normal findings on imaging was seen in 9% to 35% for CT scan and/or MRI, 4% to 11% for PET, and 6% to 15% for PET-CT. Surgical staging led to a treatment modification in 7% to 58% of cases, with a mean of 20% (Table 1).
The most common operation technique used for PALN dissection was laparoscopy (75%), 74% retroperitoneal and 26% transperitoneal, with a conversion rate of less than 2%. Laparotomy was used as operating technique in 23% of the patients. Robot-assisted PALNS was used in 2 studies, taking account for 2% of all patients. Pelvic lymph node staging (PLNS) was performed routinely in 5 studies next to PALN dissection.
All studies included in this review performed a PALN dissection (Table 2). Nine studies (41%) dissected lymph nodes up to the level of the left renal vein, and 8 studies (36%) dissected at least up to the inferior mesenteric artery (IMA). Two studies used ultrastaging in histology. The mean number of dissected PALNs was 14.2, with a range of 1 to 62 nodes. Para-aortic lymph node metastases were present in 18% (range, 8%–42%) of all patients. None of the articles described the distribution or location, above or below the IMA, of the positive PALNs. Only 7 studies reported on the size of metastatic PALNs (Table 3). On the basis of 2 studies, the proportion of grossly positive nodes (visualized at laparoscopy and confirmed by frozen section analysis) is estimated to be 11% to 50%.
Para-aortic lymph node metastases were present in 11% of stage IB2 patients, 13% of stage IIA patients, 16% of stage IIB patients, 29% of stage III patients, and 36% of stage IVA patients (Table 4).
Only 6 studies reported on solitary PALN, which is the presence of PALN metastasis in the absence of PLN metastasis. Solitary positive PALNs were found in 25% (range, 0%–70%) of patients with stage IB2 to IVA. Positive PALNs in combination with metastasized PLNs were found in 75% (range, 30%–100%) of the patients.
The mean complication rate of PALNS was 4% to 18% in the laparoscopic approach; 1 study used a solitary transperitoneal approach, with a complication rate of 4%; 3 studies used only a retroperitoneal approach, with complication rates between 6% and 19%; and 8 studies used both laparoscopic techniques, without reporting separate complication rates (Table 5). Laparotomy resulted in a complication rate of 6% to 24%. Lymphocysts are the most common complication in all approaches. The complication rate in studies with routinely performed PLNS was 4% to 24%; this rate was 4% to 13% when only PALN dissection was performed. Radiation complications, radiation enteritis accounting for 40% to 100%, were mentioned only in 4 studies, with a reported rate of 0.6% to 2.3% in studies using the retroperitoneal laparoscopic route and a rate of 51% in a study using laparotomy. The amount of lymphedema after PALNS was not mentioned.
Surgical staging has been used by clinicians during the past 3 decades for more accurate assessment of PALN involvement. This review shows that pretreatment PALNS leads to a modification of treatment in 7% to 58% of cases (Table 1). In addition, debulking enlarged positive lymph nodes may also provide therapeutic benefit next to determining the extent of the disease. Studies by Kim et al38 and Cosin et al39 showed that survival data after dissection of enlarged PALNs with adaptive adjuvant treatment are similar to survival data of patients with microscopic PALNs.
However, complications and treatment delay should be considered when performing PALNS. We found a mean complication rate of 9%. Initially, transperitoneal surgical staging was performed via laparotomy.40 However, this led to high morbidity secondary to bowel complications, particularly when surgery was followed by radiotherapy, with a complication rate of 28% to 30% and a mortality rate of 6% to 22%.5,40,41
Laparoscopic staging has the advantage over laparotomy in reduction of blood loss and faster recovery.42 Laparoscopic PALN removal can be performed either transperitoneally or retroperitoneally. The retroperitoneal approach as compared with the transperitoneal approach decreases the risk for bowel injury.12,16,43 Furthermore, the retroperitoneal approach is reported to lead to statistically significantly greater node count and fewer postoperative adhesions.44 The complication rate of the laparoscopic approach in our study ranged from 4% to 18% (Table 5), with lymphocysts being the most common, responsible for 58% of the laparoscopic complication rate. According to Gil-Moreno et al,32 this incidence could be decreased by incising the peritoneum of the paracolic gutter at the end of the procedure to allow intraperitoneal drainage of the retroperitoneal dissection area. In our study, preventive marsupialization or use of pelvic lymphatic drains was reported in 8 studies. LeBlanc et al14 and Del Pino et al27 reported a direct positive effect using this prevention technique on development of lymphocysts. Furthermore Gallotta et al45 suggested that the positive intra-abdominal pressure during laparoscopy results in closing small lymphatic vessels and consequently limiting the identification of the lymphatic leakage, which might explain the increased incidence of lymphocysts compared with laparotomy.
However, laparoscopic lymphadenectomy has a technical limitation in degrees of movement, likely leading to more conversions to laparotomy, with reported rates between 7.5% and 10.3%.43,46,47 Conversion seemed to occur more often in obese patients.48 Nagao et al43 reported that 6 of 8 patients who underwent conversion had a body mass index of greater than 30 kg/m2. In our study, conversion to laparotomy was reported in 4 studies, with a rate of 1.8%. Mortier et al28 reported a conversion rate of 26%, and Leblanc et al20 reported conversion in 6.4% of patients.
Histological analyses showed positive PALNs in 18% (range, 8%–42%) of all study patients. Solitary PALN metastases occurred in 25% (range, 0%–70%) of them. This is substantially more than the reported 1% of women by Berman et al49 and Michel et al.6 However, sampling error is a likely explanation for negative PLNs in the presence of positive PALNs.
Treatment delay has been reported to be another concerning factor when surgical staging has been used. Because of postoperative complications and logistic difficulties, the median waiting time from surgery until initiation of (chemo)radiation therapy is 10 to 21 days across studies. The effects of treatment delay due to surgical staging on survival need further investigation.
In the past decades, several imaging modalities such as CT and MRI have been used to detect PALN metastases. Criteria for lymph node involvement on CT and MRI are based on size and morphology. However, both CT and MRI are poor at detecting small volume of disease and therefore limited by low sensitivity and specificity.11,50 Accordingly, our study shows PPVs of CT and/or MRI ranging from 0% to 66%, with a false-negative rate from 9% to 35%.
Positron emission tomography or PET-CT seems to be more accurate in detecting para-aortic node metastases, with reported sensitivity from 38% to 86% and a specificity of 75%.26,51 The proportion of para-aortic nodes that were positive on histological analysis when PET or PET-CT also showed uptake in the para-aortic area was 50% to 100% (Table 1). However, several other studies reported that, in patients with normal findings on PET scan, 11% to 18% still had para-aortic metastases after evaluation of the surgical specimen.12,28 In our study, the false-negative rate for PET was 4% to 15%. Brockbank et al18 evaluated the overall effectiveness and safety of pretreatment laparoscopic staging in the literature and concluded that there was insufficient evidence that pretreatment surgical PALN assessment for locally advanced cervical cancer is beneficial. However, only 1 randomized controlled trial was included in this study.34
Recently, it has been suggested that fused PET-MRI may offer clinical advantages over PET-CT for the assessment of gynecological cancers. In contrast to CT, PET-MRI involves no associated radiation exposure and offers the high soft tissue resolution of MRI. A drawback of the PET-MRI fusion images is the misregistration due to the movement of organs between the PET and MRI studies.52,53
The effect of pretherapeutic PALN dissection or sampling is still unclear, although adaptive adjuvant treatment may lead subsequently to better survival data. Lai et al34 prospectively evaluated the role of pretreatment surgical staging for locally advanced cervical cancer. The trial showed that patients who underwent surgical staging had significantly worse survival than those without staging. The conclusion of this study is limited because of the small sample size (N = 61). Furthermore, standard treatment was not performed in 13% of patients, there was an unequal distribution of unfavorable characteristics between groups, and all patients with surgically proven PALN metastases died as a result of treatment failures or complications.
On the contrary, Gold et al51 showed a positive prognostic effect of surgical staging on both overall and progression-free survival in a multivariate analysis comparing surgical and conventional radiological (CT or MRI) staging from three phase 3 trials from the Gynecologic Oncology Group (GOG) (GOG 85, GOG 120, and GOG 165). However, this study also showed limitations by combining the randomized arms of the 3 different trials, creating a selection bias.
In our study, only 6 studies report on overall survival after PALNS. These reported survival rates show a wide diversity. In contrast to Lai et al,32 Gil-Moreno et al32 showed in their study that excellent tumor control could be achieved with pretreatment laparoscopic para-aortic lymphadenectomy without recurrences in PALNs. Moreover, they reported no significant differences in overall survival and disease-free survival in patients treated for microscopic PALN metastases compared with patients with negative PALNs, suggesting a therapeutic benefit of staging lymphadenectomy.
Recently, Frumovitz et al54 announced their international multicenter phase III trial (LiLACS study) with the objective of determining whether pretherapeutic laparoscopic surgical staging followed by tailored chemoradiation improves survival as compared with PET/CT radiological staging alone followed by chemoradiation.
Pretreatment surgical staging of PALNs seems to be effective and beneficial. Positron emission tomography or PET-CT seems to be the most accurate imaging method in detecting PALN metastases so far, although microscopic tumor volumes are still missed. At the moment, surgical staging needs to be considered in the assessment of para-aortic involvement and treatment of advanced cervical cancer. Pretreatment surgical staging is beneficial by allowing adequate histological evaluation of the retrieved PALNs and leading to a modification of treatment in 7% to 58% of cases.
However, postoperative morbidity and treatment delay should be taken in mind. Using a retroperitoneal approach may reduce postoperative complications, especially when using special techniques for the prevention of lymphocysts. Large randomized controlled trials are needed to provide more accurate information about the efficacy and survival rates.
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0. For the complete list of references, please contact Ruud.Bekkers@radboudumc.nl
© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.