Summary of main results
We found one RCT (Lai 2003) addressing the question of pre-treatment para-aortic lymph node assessment in locally advanced cervical cancer. This trial aimed to compare clinical staging of locally advanced cervical cancer; CT or MRI to determine para-aortic nodal status, with surgical staging. The surgical approach was either LAP or EXP for para-aortic nodal assessment. The trial found that women who underwent surgical staging had a significantly higher risk of death and persistent or recurrent disease than women who underwent clinical staging (the HR for death and persistent or recurrent disease, for surgical versus clinical staging, was 1.50 (95% CI 1.04 to 2.17) and 1.71 (95% CI 1.17 to 2.49), respectively). There was no significant difference between the number of women who experienced severe toxicity in the two staging groups. OS and PFS, operating time, blood loss, duration of operation and lymph node yield was not significantly different in the laparoscopic versus extraperitoneal surgical approach arms.
This RCT suggests that pre-treatment surgical para-aortic lymph node assessment in locally advanced cervical cancer is detrimental to patient survival. However, there are a number of factors that may have influenced the results and therefore potentially downgrade the value of this evidence. Apart from time from randomisation to starting radiotherapy, there were no statistically significant baseline imbalances between the clinical and surgical staging groups for any known prognostic factors. However, a higher proportion of women with poor prognostic pre-treatment features were in the surgical compared to the clinical staging arm; 17/32 (53%) in the surgical staging arm had FIGO stage III disease compared to 11/29 (38%) in the clinical staging arm. In the surgical arm, 8/32 (25%) had a primary tumour > 6 cm, in the clinical arm this was 5/29 (18%). ADs occurred more in the surgical arm; 5/32 (16%) versus 2/29 (7%) in the clinical arm. Although only histology (AS versus ACC) had a significant impact on OS when prognostic factors were investigated by the trial authors.
The longer time from randomisation to starting radiotherapy in the surgical versus the clinical staging arm (median 20 days, range 10 to 46 days in the surgical arm versus a median of 11 days, range 2 to 52 days in the clinical staging arm) may have had an effect on outcomes. However, although there was a significant difference between the two groups at baseline, the authors state that there was no significant difference in time to starting radiotherapy between survivors and non-survivors (P value = 0.90, exact numbers for this analysis not given). The fact that a smaller, non-significant percentage of women in the surgical arm received concurrent chemotherapy with their radiotherapy may have influenced the PFS and OS data; 15/32 (47%) women in the surgical arm had concurrent chemotherapy versus 19/29 (65%) in the clinical staging arm.
The para-aortic lymph node yield was relatively low: mean of 6.1 with SD of 2.2 for those staged via the LAP route and 5.9 with SD of 2.9 for those in the EXP arm. It may be that the node dissection was incomplete and therefore insufficient to exert a positive effect on survival data.
Overall the results of this one RCT are not sufficient alone to confirm or refute that there is a survival benefit from pre-treatment para-aortic lymph node assessment in locally advanced cervical cancer.
Overall completeness and applicability of evidence
Overall, the quality of the evidence was low (GRADE Working Group 2004). We only identified one RCT that met our inclusion criteria and no good-quality non-randomised studies with concurrent comparison groups to test the robustness of findings from this one trial; we have identified insufficient evidence to address the objectives of the review. The overall conclusions of the review are weak and there is no external validity. However, we recognise that within clinical practice the findings from a number of non-randomised case series on surgical staging of para-aortic nodal disease in advanced cervical cancer will continue to influence practice.
Although we specified QoL as an outcome of interest, this was not reported in the RCT identified, or in any of the excluded non-randomised trials. QoL after cancer treatment is an extremely important outcome; treatment-related morbidity often degrades the quality of a person's remaining time alive.
Quality of the evidence
The one RCT identified analysed the outcome of 61 women. Women were assigned to staging groups using an appropriate method of sequence generation (although it was unclear whether the allocation had been concealed). Eight women had a protocol violation; one woman randomised to the clinical staging arm had an EXP lymph node assessment. One woman randomised to have LAP surgical staging in fact had an EXP approach. In each arm there were two women who had no or incomplete radiotherapy. Two women with documented para-aortic node metastasis did not receive a radiation field covering the para-aortic nodes. However, analyses were based on an intention-to-treat basis, which generally is less biased than the per-protocol approach. There was no loss to follow-up.
Although this RCT suggests that the pre-treatment surgical para-aortic lymph node assessment in locally advanced cervical cancer is detrimental to patient survival, the number of women studied was small and, as identified above, there are a number of confounding factors that may have influenced the results.
The trial was at a moderate risk of bias, since it did not report adequate concealment of the randomisation sequence from healthcare providers and participants, or blinding of outcome assessors. Inadequate concealment of allocation and lack of blinding are often associated with an exaggeration of the effects of treatment (Moher 1998; Schulz 1995). The evidence on OS is more robust than that for PFS, since blinding of outcome assessors is of less relevance for death than for disease progression.
The trial reported HRs, which are the best statistic to summarise the difference in risk in two treatment groups over the duration of a trial, when there is "censoring", that is, the time to death (or disease progression) is unknown for some women as they were still alive (or disease free) at the end of the trial.
Potential biases in the review process
A comprehensive search was performed, including a thorough search of the grey literature and all studies were sifted and data extracted by at least two review authors independently. We restricted the included studies to RCTs as they provide the strongest level of evidence available. Hence we have attempted to reduce bias in the review process.
The greatest threat to the validity of the review is likely to be the possibility of publication bias, that is, studies that did not find pre-treatment surgical para-aortic lymph node assessment in locally advanced cervical cancer to have been effective may not have been published. We were unable to assess this possibility.
Agreements and disagreements with other studies or reviews
Pre-treatment assessment of para-aortic nodal status in locally advanced cervical cancer allows the option of tailoring the radiotherapy field to include the para-aortic nodal tissue or not. Prophylactic extended-field radiotherapy for all those with advanced-stage disease has not conclusively been shown to confer a survival advantage, but does significantly increase treatment-related morbidity, particularly gastrointestinal complications (Chatani 1995; Haie 1988; Rotman 1995; Small 2007). Therefore, being able to accurately identify those women who do have para-aortic nodal disease and tailoring extended-field radiotherapy to this subgroup of women with locally advanced cervical cancer is an attractive proposition.
Non-invasive radiological methods for detection of para-aortic nodal involvement remain unsatisfactory. MRI and CT have a similar diagnostic accuracy with reported false-negative rates of 20% to 50% to detect those women with macroscopic lymph node metastasis (Choi 2006; Subak 1995). PET seems to be more successful at detecting involved para-aortic nodes; however, reported sensitivities range from as low as 38% and up to 86% (Gold 2008). One conference report confirmed the poor sensitivity of PET at detection of small volume node disease; 22% if histologically confirmed para-aortic nodal metastasis was less than 5 mm in size (Leblanc 2010). Additionally, the improved detection of extra-pelvic metastatic disease by PET over MRI may not be translated into a survival advantage (Tsai 2010). One meta-analysis involving data on lymph node status in 5042 women with cervical cancer found that the pooled positive likelihood ratios (and 95% CI) were 15.3 (7.9 to 29.6) for PET, 6.4 (4.9 to 8.3) for MRI and 4.3 (3.0 to 6.2) for CT. The pooled negative likelihood ratios (and 95% CIs) were 0.27 (0.11 to 0.66) for PET, 0.50 (0.39 to 0.64) for MRI and 0.58 (0.48 to 0.70) for CT (Selman 2008).
Sentinel lymph node (SN) biopsy may be a minimally invasive, accurate assessment of lymph nodes status. A systematic review of the diagnostic performance of SN detection for assessing the nodal status in early-stage cervical carcinoma showed that the combination of 99mTc and a blue dye for SN biopsy in these cases is a reliable method to detect lymph node metastases (Van De Lande 2007). No studies have looked at the potential role of SN assessment in advanced cervical cancer.
Therefore using a surgical pre-treatment assessment of para-aortic nodal status remains of interest, despite the potential detrimental effects of surgical staging observed in the trial of Lai 2003. A number of case series report on the safety and feasibility of surgical lymph node assessment, which then allows tailored external beam radiotherapy (Berman 1977; Chu 1997; Cosin 1998; Goff 1999; Hertel 2002; Holcomb 1999; LaPolla 1986; Leblanc 2007; Marnitz 2005; Podczaski 1989; Sonoda 2003; Weiser 1989). None of these case series included a concurrent comparison group so would not have met the inclusion criteria for this review even if non-randomised studies been included.
Initial reports on the use of surgical staging for the purpose of defining the need for extended-field radiation identified that 2.5% to 6.8% of women undergoing pre-treatment staging laparotomy for cervical cancer will have a survival benefit as a consequence of radiotherapy treatment modifications based on surgical findings (LaPolla 1986; Tewfik 1982). However this was at the expense of significant morbidity. Reports in the 1970s and 1980s looked at the use of extraperitoneal staging to minimise the risk of enteric morbidity. A study in the 1970s compared 33 women who had transperitoneal approach to 40 women who had a retroperitoneal approach to operative evaluation, including para-aortic lymphadenectomy, prior to radiotherapy (Berman 1977). The extraperitoneal approach resulted in a greater mean number of pelvic and para-aortic lymph nodes sampled; 23.1 versus 11.4. Those who had a transperitoneal approach had a 30% small bowel complication rate following radiotherapy, all of which required surgical correction. In comparison, for those with the retroperitoneal approach the small-bowel-related morbidity rate was only 2.5%. The two surgical approaches were not studied concurrently; the transperitoneal approach was the earlier operative technique applied. Similarly, the authors of LaPolla et al., in their retrospective cohort study of two surgical methods for pre-treatment evaluation of para-aortic nodes, observed a higher rate of small bowel complications following radiotherapy that required surgical correction for women who had a transperitoneal surgical exploration versus those who had an extraperitoneal surgical assessment; 9% versus 0% (LaPolla 1986).
Weiser 1989 compared 128 women who had extraperitoneal surgical staging, including selective para-aortic lymphadenopathy followed by pelvic irradiation, with or without para-aortic irradiation with 156 women who had transperitoneal surgical staging. Those with confirmed para-aortic metastasis or thought to be at risk of undetected occult para-aortic metastasis received radiation to the para-aortic area. Surgical complications and pelvic complications secondary to radiotherapy were similar in each group. In agreement with other studies, bowel obstruction and non-obstructive enteric injuries were observed significantly more often in those who had transperitoneal staging compared to those who had extraperitoneal surgical staging (18/156 (11.5%) vs. 5/128 (3.9%), P value = 0.03).
With the published evidence, as outlined above, suggesting that extraperitoneal surgical staging minimised morbidity, the shift within published literature was then to establish whether such an approach to pre-treatment assessment in locally advanced cervical cancer affords a survival benefit.
Cosin 1998reported the results of a retrospective review of 266 women with stage IB to IV cervical carcinoma whom all had an EXP pelvic and para-aortic lymphadenectomy prior to receiving radiotherapy. Women were divided into groups based on their lymph node status. Group A had negative lymph nodes; group B had resected, microscopic lymph node metastases; group C had macroscopically positive lymph nodes that were resectable at the time of surgery and group D had unresectable lymph nodes. All women received standard pelvic radiotherapy. Women with lymph node metastases received extended-field irradiation. The use of concurrent and adjuvant chemotherapy increased over the time of this review. Although there was no survival difference between women in group C who received chemotherapy and those who did not, 133/266 (50%) women had histologically confirmed lymph node metastasis. OS rates were not reported. The disease-free survival at 10 years was 68% for group A, 35% group B, 46% group C and 0% (by three years) for group D. These data suggest that actually removing macroscopically involved lymph nodes confers a survival advantage. Whether this is due to removing the bulk of the disease or ensuring the radiation field includes confirmed nodal disease, or both, is unclear.
The aim of Holcomb 1999's retrospective review of 274 women with stage IIB-IVA cervical cancer was to determine the effect of pre-treatment surgical staging on survival. Eighty-nine women had pre-treatment staging laparotomy and 172 women underwent clinical staging. Para-aortic metastases were identified in 11/89 (12.3%) and intra-abdominal metastases were found in 4/89 (4.5%) women who had a staging laparotomy. Extended-field radiotherapy or systemic chemotherapy, or both, were given in these cases. The median survival of women who had a staging laparotomy was longer than that of women who had clinical staging; 29 months versus 19 months (P value = 0.01). Multivariate analysis controlling for both stage and age showed pre-treatment staging laparotomy to be a significant predictor of survival in this study (P value = 0.03).
The retrospective single institute case series by Goff 1999reported on the impact of surgical staging over a five-year period for 98 women with locally advanced cervical cancer. A total of 86/98 women underwent surgical staging with removal of pelvic lymph nodes followed by removal of common iliac or para-aortic, or both, lymph nodes. The highest lymph nodes removed were sent for frozen section, and if positive for metastatic disease, scalene node dissection was performed through a separate incision. The surgical approach was retroperitoneal for 61/86 (69%) women, laparoscopic for 18/86 (21%) and intraperitoneal for 7/86 (10%) women. Based on the results of surgical staging, 37/86 (43%) women had a modification to the plan for standard pelvic radiation; 27/86 (32%) received extended-field radiation. The authors did not report the factors that determined the use of extended-field radiation for these 27 women. Of significance, the type of radiotherapy, pelvic versus extended field did not affect survival. Ten from 86 (11%) women surgically staged were identified for palliative treatment only, due to scalene metastasis or ovarian metastasis with extensive intraperitoneal disease. They were therefore spared the side effects of aggressive treatment with no chance of cure. So although this study did not show any survival benefit with the information obtained from surgical pre-treatment assessment of para-aortic node, it did identify a possible role of surgical staging in ensuring that women are not inappropriately treated with curative intent.
In order to potentially further reduce surgical-related morbidity, laparoscopic para-aortic nodal assessment has now come to the forefront of research on the pre-treatment assessment of para-aortic lymph node status in locally advanced cervical cancer (Hertel 2002; Leblanc 2007; Marnitz 2005; Querleu 1993; Sonoda 2003; Vergote 2002).
Hertel 2002reported their single institute case series on laparoscopic surgical staging of 109 women with stage IB2 or higher stage cervical cancer. A total of 101 women had para-aortic lymphadenectomy with mean of 10.4 (range 1 to 50) lymph nodes removed. Twenty-one of 101 (20.8%) had positive para-aortic lymph nodes. Four of 101 (3.7%) women had an intraoperative complication; two vascular injuries and two ureteric injuries. Two of 101 (1.8%) required an intra-operative blood transfusion. Two of 101 (1.8%) women had postoperative complications; one retroperitoneal lymphocoele and one retroperitoneal haematoma. False-negative or false-positive results of MRI and CT imaging were identified on the basis of laparoscopic findings in 24/101 (22%) women and led to a change in treatment plans. Ten women had false-positive imaging for para-aortic lymph node metastasis, extended-field radiotherapy had been planned; eight of these were treated with radical hysterectomy and two had pelvic radiotherapy. Planned operative management was changed to adjuvant chemotherapy in 14 women; in two women due to intraperitoneal metastases (palliative setting) and to combined chemoradiotherapy in 12 women (positive para-aortic lymph nodes that had been negative by imaging techniques). Thus for these women, extensive surgery was avoided. No OS or PFS data were reported.
Marnitz 2005 reported on a retrospective case series of 84 women with locally advanced cervical cancer who had transperitoneal laparoscopic surgical staging, including right-sided para-aortic lymphadenectomy and infra-mesenteric left-sided para-aortic lymphadenectomy (and then para-aortic lymphadenectomy up to infrarenal level if these lymph nodes contained metastasis on frozen section) prior to treatment with chemoradiotherapy. There were no intra-operative complications. Thirteen of 84 (15.5%) women developed postoperative lymphocysts > 5 cm, eight of whom required laparoscopic drainage. Thirty-two of 84 (38%) women had histologically confirmed para-aortic nodal disease. The authors made no comment on how or whether nodal involvement was assessed preoperatively. Thirty-six of 84 (43%) women were upstaged according to the histological findings following laparoscopic staging. Downstaging was not necessary in any woman following laparoscopic evaluation. Multivariate analysis identified that removal of more than five positive para-aortic lymph nodes was associated with significant improvement in OS compared with those who had fewer than five positive nodes removed (P value = 0.01). Removal of five or more involved pelvic or para-aortic lymph nodes took survival back to that for those with histologically negative nodes.
The laparoscopic extraperitoneal approach potentially combines the benefits of an extraperitoneal approach with those of minimally invasive surgery. This was confirmed by the single institute case series of 111 women with FIGO stage IB2 to IVA cervical cancer who had laparoscopic extraperitoneal surgical staging (Sonoda 2003). They had no radiologically enlarged para-aortic lymph nodes. The mean operative time was 157 (SD 46) minutes. The mean lymph node count was 19 (SD 12). There were no intra-operative complications. Fourteen of 111 (13%) women had a postoperative complication, of which five required a second procedure under anaesthesia. Thirty of 101 (27%) women were confirmed to have lymph node metastasis. After an average (unclear whether this was mean or median) follow-up of 16.5 months, mean survival for the node-negative group was 38.6 months compared to 26.5 months for the node-positive group. Six of 30 (20%) node-positive women developed distant metastasis, compared to 5/81 (6%) node-negative women (P value = 0.05).
Leblanc 2007 reported a single centre case series of 184 women with stage IB2–IVA cervical cancer who had pre-treatment laparoscopic staging procedure, including transperitoneal abdomino-pelvic exploration and extraperitoneal bilateral infrarenal para-aortic lymph node dissection. They had no evidence of extrapelvic disease on pre-operative imaging; MRI or CT, or both. Women were then treated with definitive radiotherapy tailored according to the staging results; those with negative para-aortic lymph nodes were managed with external beam radiotherapy to the pelvis followed by intracavitary brachytherapy with intent to cure. Women with metastatic disease to para-aortic lymph nodes received extended-field external beam radiotherapy followed by intracavitary brachytherapy, with intent to cure. The study ran from 1997 to 2004, where from 1999 women also received concurrent platinum-based chemotherapy. Those with carcinomatosis were given platinum-based chemotherapy with palliative radiotherapy. Three of 184 women had peritoneal carcinomatosis at the initial diagnostic laparoscopy so did not proceed to lymphadenectomy. Lymphadenectomy was abandoned in eight women; five due to macroscopically positive fixed nodes and three due to obesity. Four of 181 (2.2%) women had intra-operative complications and 19/181 (10.5%) had postoperative complications. Fourteen of these were symptomatic lymphocysts in the first 104 women. Therefore the surgical technique was amended to include the creation of a transperitoneal opening in the left paracolic gutter for the final 77 women; with a reduction in lymphocyst formation to 3/77 (3.8%). Forty-four of 181 (24.3%) women had histologically confirmed para-aortic nodal disease. Histological findings from pre-treatment staging affected the therapeutic approach taken in 96/184 (52.1%) women. Three women with stage II–IV cervical cancer, identified to have peritoneal carcinomatosis, were managed with full-dose chemotherapy and pelvic irradiation. Of the 67 women with stages IB2 and IIA disease who would have received pelvic radiation only, 14 (20.8%) had positive para-aortic nodes and therefore received extended-field radiation. These women would have been under-treated if treatment planning was based on clinical staging alone. Conversely, 79/109 (72.4%) women with stages IIB–IVA disease had negative para-aortic lymph nodes and therefore received only pelvic radiotherapy. These women would have been over-treated with prophylactic extended-field radiation if treatment planning was based on clinical staging. In this series, OS and disease-free survival was 58.3% (95% CI 48.3 to 68.3) and 56.3% (95% CI 46.9 to 65.7), respectively at five years. A Cox proportional hazards model revealed that survival was significantly worse when tumour size was > 5 cm (P value = 0.007) and when para-aortic nodes were positive (P value = 0.02). There was no survival difference between those with node-negative disease who received a pelvic treatment alone and women with microscopic nodal disease (≤ 5 mm) managed with definitive extended-field (chemo)radiotherapy; this suggests a therapeutic benefit in para-aortic node dissection.
Additionally, Occelli 2000 demonstrated in a porcine study, decreased formation of adhesions after the laparoscopic extraperitoneal approach when compared to the transperitoneal laparoscopic approach. Of note, the majority of adhesions formed after the extraperitoneal approach were located outside the para-aortic external radiation field. Intra-abdominal adhesion formation is a major causative factor for radiation-induced small-bowel injury after surgical staging, so means of reducing adhesion formation are likely to impact on reducing morbidity associated with pre-treatment surgical staging for locally advanced cervical cancer.
Gold 2008 reported the combined results of three RCTs retrospectively, using women from one of the randomisation arms in each of the contributing studies. Women with cervical cancer who had negative para-aortic lymph nodes as identified by pre-treatment surgical staging were compared with those who had radiographic exclusion of para-aortic lymph node metastases before they received treatment with pelvic radiation and brachytherapy plus cisplatin-based chemotherapy. The women were pooled from three Gynecologic Oncology Group (GOG) RCTs (Lanciano 2005; Rose 1999; Whitney 1999). GOG 85 (Rose 1999) was a randomised trial of radiotherapy in combination with three concurrent chemotherapy regimens; cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone; in women with locally advanced cervical cancer. All women were required to have undergone extraperitoneal para-aortic lymphadenectomy. GOG 120 (Whitney 1999) compared primary radiotherapy plus hydroxyurea versus irradiation plus fluorouracil and cisplatin for women with locally advanced cervical carcinoma. All women underwent para-aortic lymphadenectomy via a retroperitoneal approach. GOG 165 (Lanciano 2005) was a comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation for women with advanced cervical cancer. Surgical para-aortic lymph node assessment was optional, no information was given by the authors on how women were selected for surgical nodal assessment. The Gold 2008study analysed data from 685 women; 177 from GOG 85 in the radiotherapy and cisplatin plus 5-fluorouracil arm; 176 from GOG 120 in the radiotherapy and cisplatin arm or radiotherapy and cisplatin with 5-fluorouracil plus hydroxyurea arm; and 159 from GOG 165 in the radiotherapy plus cisplatin arm. Staging was completed surgically in 555 women (including 29 women on GOG 165 in which the procedure was optional) and radiographically in 130 women. Women in the radiological assessment group had better performance status (P value < 0.01), less advanced stage (P value = 0.023), and smaller tumour size (P value = 0.004) compared with those in the surgical assessment group. Women with stage III and IV disease in the surgical group had better four-year PFS (48.9% versus 36.3%) and OS (54.3% versus 40%) compared with those in the radiological group. Actual numbers for the survival data were not reported. Overall, those in the radiological evaluation group had a poorer prognosis than those in the surgical assessment group; the HR for disease progression was 1.35 (95% CI 1.01 to 1.81) and the HR for death was 1.46 (95% CI 1.08 to 1.99). However, as women were not randomised in terms of surgical para-aortic lymph node assessment, selection bias is likely to be a significant problem and therefore the validity of these results in respect to the objectives of this review is low.
The non-RCT published data, as discussed above, suggests that laparoscopic pre-treatment staging and assessment of para-aortic lymph nodes in locally advanced cervical cancer is more accurate than currently available imaging modalities. It is safe with low intra- and postoperative morbidity; evidence suggests that the laparoscopic approach can eliminate major postoperative complications, with an overall complication rate for laparoscopic staging less than 3% compared to 10% to 15% following transperitoneal laparotomy (Hertel 2002; LaPolla 1986; Leblanc 2007; Sonoda 2003). However, the included RCT in this review did not find any significant difference in the postoperative morbidity between these two techniques. The laparoscopic approach results in fewer postoperative adhesion formation, and therefore less bowel-related complications if the woman goes on to receive extended-field radiotherapy compared to transperitoneal laparotomy. Laparoscopic staging appears to be comparable to laparotomy techniques in terms of node count and results in treatment modification 22% to 58% of the time (Goff 1999; Hertel 2002; Lai 2003; Leblanc 2007). Complete debulking of involved para-aortic lymph nodes appears to translate into a survival advantage compared to when no nodal debulking is performed. Surgical pre-treatment assessment of para-aortic lymph nodes in locally advanced cervical cancer results in treatment modifications for 22% to 58% of women; although it is not confirmed that this results in a positive impact on survival.