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
Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Cervical cancer; Para-aortic; Lymphadenectomy; Staging; Imaging