Role of laparoscopy in initial tumour staging in advanced epithelial ovarian cancer: a systematic review

Introduction

Epithelial ovarian cancer (EOC) is the leading cause of gynaecologic cancer death in Western countries [1]. A majority of women with EOC are diagnosed at advanced stage of disease. Conventional preoperative staging in EOC consists of medical history, complete physical examination, assessment of CA125 and CEA serum levels, chest X-ray and contrast-enhanced abdominopelvic CT.

The guideline-recommended treatment for these patients is primary debulking surgery (PDS) followed by combination platinum-based chemotherapy [2, 3]. In a Cochrane review, there were no RCTs identified that were designed to evaluate the effectiveness of surgery when performed as a primary procedure in advanced stage ovarian cancer. There was a high risk of bias due to the retrospective nature of these studies where, despite statistical adjustment for important prognostic factors, selection bias was still likely to be of particular concern [4].

However, there is large agreement that completeness of cytoreduction (CR) during PDS is the most important prognostic factor in EOC [5] and that complete resection of all macroscopic disease is the objective whenever PDS is performed [6]. However, CR during PDS may require extensive surgery with a subsequent higher risk of mortality and morbidity [7]. Against this background, it has to be noted that, in the Cochrane review [8], adverse events, quality of life and cost-effectiveness were not reported by treatment arm or to a satisfactory level in any of the studies [4]. Moreover, despite maximal surgical effort, complete PDS is not always possible and 30 %–70 % of patients are left with gross residual disease after PDS, dep both on extent of disease and quality of CR [9]. In those cases, neoadjuvant chemotherapy followed by interval debulking surgery is currently recommended by US SGO and ASCO guidelines [10].

Futile (“open and close”) laparotomy (FL) should be prevented in women with EOC: not only such exploration has no prognostic benefit for the patient, but it might be harmful since it is associated with pain, complications, intraoperative blood loss, hospital stay, interruption of diet intake, delays the start of neoadjuvant/palliative chemotherapy and significant costs [11].

Unfortunately, in spite of recent technological progress, preoperative contrast-enhanced CT of the abdomen and pelvis is still not able to demonstrate small volume (<5 mm) extra-ovarian deposits on bowel serosa, mesentery and peritoneum especially in the absence of ascites [12]. Predictive value of CT for CR has been shown to be limited in EOC, because it underestimates extent of peritoneal disease, in particular in those women with expected early-stage EOC. Overall area under the receiver-operating characteristic (ROC) curve for score predicting suboptimal CR was 0.761 with sensitivity, specificity, and positive and negative predictive values of 70.6 %, 73.2 %, 68.7 %, and 91.9 %, respectively [13].

Since CT-scan alone is not able to prevent effectively futile laparotomies, laparoscopic staging (LS) is increasingly incorporated into the early management of EOC (Figure 1) in order to better predict feasibility of complete PDS. The hope is that LS might better predict the feasibility of CR in EOC than CT-scan alone, and thus prevent futile explorative laparotomies [14]. The rationale for this approach is that LS is minimally invasive, has a low complication rate, is not related to significant pain and does not cause significant blood loss. Moreover, LS is a short-stay procedure [15]. Finally, biopsies taken during LS allow confirmation of diagnosis and molecular analysis [16]. Thus, LS appears to many gynaecologists to be a reasonable additional option in the initial staging of women with AEOC. On the other hand, LS is an additional surgical intervention requiring general anaesthesia. The overall risk of complications of LS is reported between 1 % and 5 % [17], port-site recurrences have been reported in up to 31 % cases [18] and LS causes additional costs for the health system.

Figure 1:

Clinical pathway and diagnostic test (staging laparoscopy).

A Cochrane review published in 2014 (last edited in June 2016) investigated if performing a LS after the conventional diagnostic workup of patients suspected of advanced EOC (AEOC) is accurate in predicting the resectability of disease [19]. This review did not allow to draw firm conclusions: first, the number of studies (seven) was fairly limited. Second, due to the difference in prevalence in CR between studies, there was a wide range in negative predictive values between studies. Third, five studies did not perform the reference standard (explorative laparotomy) in all patients.

Thus, the jury is still out and, at the present point of time, discrepancy exists between guidelines: Whereas the US NCCN current guidelines recommends LS as part of the diagnostic workup in AEOC (evidence level 2B) [20], the current German S3-guideline explicitly discourages the use of LS in EOC [3]. Since 2014, publication of a randomized controlled trial [14] and of a larger cohort study [21] contributed additional information on this question. This systematic review will review systematically data available, and suggest that LS should now be recommended as part of the initial diagnostic workup in women with advanced EOC (AEOC).

Materials and methods

This systematic review agrees to the guidelines outlined in the preferred reporting items for systematic reviews and meta-analyses statement (PRISMA), which is designed to improve manuscript quality [22]. The PRISMA statement was used in conjunction with the PRISMA explanation and elaboration document [23] and PRISMA abstracts guidelines [24]. A PRISMA flow chart is included, depicting the flow of information through the different phases of this systematic review.

Results

The literature search using the search strategy described above identified 236 studies. The search process is summarized in Figure 2. Ultimately, nine articles were included in these review [14, 21, 22, 23, 26, 27, 28, 29, 30] and summarized in Table 1. Of the articles included, a single one was a randomized controlled trial and two were prospective studies. The remaining trials were retrospective studies or their design was not fully reported. Two studies reported about the same patient cohort, the first one for analysing accuracy of LS, the second one for validating a scoring system [28, 29].

Figure 2:

Flow diagram according to PRISMA guidelines: results of the search for clinical studies evaluating the diagnostic accuracy of staging laparoscopy (LS) to predict complete cytoreduction (CR) during primary debulking surgery (PDS) in women with advanced epithelial ovarian cancer (AEOC).

Table 2 shows the methodological quality and applicability of the selected studies. Two studies had a high level of quality with low risk of bias and no significant concerns regarding applicability of results [14, 21]. An applicability concern in the study of Rutten could be ruled out by selecting for analysis only the women with FIGO stage IIIc/IV EOC [14]. Two additional studies had a low risk of bias but some applicability concerns, because early-stage EOC patients were included [27, 30]. The other studies had a significant risk of bias due to patient selection, or to applicability concerns (e. g. in the study of Vergote et al. [26] a cut-off for CR of 0.5 cm, whereas all other studies had a cut-off of 1 cm).

Altogether, these nine studies included 778 patients who received LS (index test). Out of these patients, explorative laparotomy was completed in 592 (76 % patients), so that the reference test (laparotomy) was not performed in 21 % patients, or the reference test was performed in only three out of nine studies. Therefore, in six studies, it was not possible to determine sensitivity, specificity or positive predictive value of LS.

In six studies focussing on the value of LS for predicting incomplete CR, PPV was between 0.69 and 1.0 (Table 3). However, it has to be noted that, in the study with the best result [27], PPV was overestimated since 13 undetermined cases were excluded from analysis.

In the three studies examining the value of a PIV for predicting incomplete CR (FL), sensitivity of the index test (LS with PIV ≥8) was between 46% and 70 %, and specificity between 89 % and 100 % (Figure 3). To allow this analysis, another cut-off value (PIV ≥8) than the original value (PIV ≥10) was selected in the study of Petrillo et al. [21].

Figure 3:

Accuracy of predictive index value (PIV) with a cut-off ≥ 8 to predict unresectable disease in 402 women with advanced epithelial ovarian cancer (AEOC).

Importantly, the proportion of patients that received CR during PDS differed widely between studies (from 50% to 91 %, Table 1), which might explain in part the large differences observed in sensitivity and specificity between studies (Figure 4). Further factors might be bias in patient selection (depending on the quality of the radiological work-up), the nonavailability of the reference test in about one-fourth patients and differences in the definition of the target condition (various definitions of residual disease after PDS).

Figure 4:

ROC curve of the accuracy (sensitivity vs. specificity) of predictive index value (PIV) with a cut-off value of ≥ 8 in advanced epithelial ovarian cancer (AEOC) for predicting non-resectability (futile laparotomies) during primary debulking surgery (PDS). Calculation based on 3 studies (Brun 2009, Fagotti 2008, Petrillo 2015).

Only the patients having received LS in the prospective randomized trial of Rutten were included in this review. Against this framework, it is important to note that, in this study, FL occurred in 10 (10 %) of 102 patients in the laparoscopy group versus 39 (39 %) of 99 patients in the primary surgery group (relative risk, 0.25; 95 % CI, 0.13–0.47; p<0.001).

Discussion

Determining the best therapeutic strategy is essential in women with EOC: One the one hand, complete CRS should be achieved but, on the other hand, the number of futile laparotomies should be minimal. Thus, the key is to select patients in whom complete CRS can be achieved, first in primary and if not possible, in the interval setting [31, 32, 33, 34].

Whereas the evidence for inclusion of LS in the initial staging of AEOC is now given, interpretation of this evidence should remain careful.

Progress in CT imaging technology allows better identification and characterization of metastatic lesions in clinical practice. For predicting incomplete CR (FL in AEOC, contrast-enhanced CT has recently been reported to have a sensitivity, specificity, PPV and NPV of 70.6 %, 73.2 %, 68.7 %, and 91.9 %, respectively) [13]. Specific radiologic criteria predicting incomplete CR were: lesions in the splenic hilum/ligaments (OR 1.36), retroperitoneal lymph nodes above the renal hilum (including supradiaphragmatic), (OR 1.31), gastrohepatic ligament/porta hepatis lesions (OR 1.44), diffuse small bowel adhesions/thickening (OR 1.12), lesions in the gallbladder, fossa/liver intersegmental fissure (OR 2), moderate-severe abdominal ascites (OR 2.21), lesser sac lesions>1 cm (OR 2.24) and lesions in the root of the SMA (OR 4.06). All ORs were significant with p<0.01. ROC curveswere generated to compare differentmodels’ accuracy in predicting gross RD. The eight CT criteria combined showed an AUC of 0.694. These figures do not to differ considerably from the figures obtained with LS (Table 4). It has to be noted, however, that, predictive value of CT for CR appears highly variable, depending on the stage of disease (NPV between 45 % and 96 %) [35] and probably on the technology available and on the expertise available.

Although evidence available suggests that SL is largely equivalent to explorative laparotomy for staging the extent of intraperitoneal spread in EOC, a significant number of women cannot be evaluated by laparoscopy. For example, the presence of adhesions can prevent the access to the abdomen, or impair complete exploration of the peritoneal cavity. For example, in the study of Fagotti et al. [27], definitive conclusions on the possibility of optimal CR could not be drawn in 13/64 patients. Moreover, PIV score is focused on the assessment of intraperitoneal diffusion of the disease, not being able to properly evaluate the retroperitoneal space, which prevents complete CR in many cases.

The rate of complications after LS is low, but some of these complications can be severe [36]. The critical phase of LS is the abdominal access, and vessel and bowel injuries have been reported. The rate of abdominal access injuries varies from 5 to 30 per 10,000 procedures: 4.4 per 10,000 for bowel injuries, 3.1 per 10,000 for vascular injuries, and 3 per 100 for injuries related to umbilical trocar insertion [37].

A specific adverse event after LS are port site tumour recurrences, with a reported clinical incidence of 2 % [29], 3 % [26], 3 % [14] and 6 % [23] in this systematic review. Subclinical, histological port site recurrences might be more frequent [18]. Port-site recurrences after LS in AEOC probably have no impact on survival [38]. Preventive measures such as closure of the fascia might reduce their incidence [39]. Finally, placement of the abdominal access ports on the midline could help to control this potential complication of LS.

At least seven systems with different cut-offs (PIV) have been proposed for scoring the extent of intraperitoneal disease (reviewed in 41). However, the only randomized study showed superiority of LS over conventional staging alone in predicting incomplete CR without any PIV [14]. In fact, using a prediction model does not increase the sensitivity and might result in more patients unsuccessful debulking surgery [19]. Finally, completeness of might be is more related to the surgical effort than to the extent of the disease [40].

A recent randomized study evaluated the cost-effectiveness of SL prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery in 201 patients suspected of advanced stage ovarian cancer. SL generated costs of € 1400 per intervention but reduced the proportion of futile laparotomies from 39 % to 10 %. Overall costs of both strategies were found to be comparable. No significant difference in quality adjusted life years(QALYs) (utility=0.01; 95 % CI 0.006–0.02) was observed [15].

Taken together, the evidence available from this systematic review supports the inclusion of additional LS to the conventional initial diagnostic workup in women with AEOC. The conclusion on this systematic review is in accordance with the conclusion of the only RCT available in the field [14], and with the recommendation of the current US NCCN guideline [20].