Annals of Oncology Advance Access originally published online on October 19, 2005
Annals of Oncology 2006 17(2):189-199; doi:10.1093/annonc/mdj013
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© 2005 European Society for Medical Oncology
review |
The current role of staging laparoscopy for adenocarcinoma of the pancreas: a review
1 Tulane Center for Minimally Invasive Surgery, Tulane University Health Sciences Center, New Orleans, LA; 2 Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX; 3 Department of Radiation Medicine, Oregon Health and Science University, Portland, OR, USA
* Correspondence to: Dr C. R. Thomas Jr, Professor and Chairman, Department of Radiation Medicine, Oregon Health and Science University, Portland, OR, USA. Tel: +1-210-616-5684; Fax: +1-210-949-5085; E-mail: cthomas{at}ctrc.net
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Abstract |
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Top
Abstract
introductionIn the absence of metastatic disease patients with localized or locally advanced pancreatic cancer can benefit from surgical resection or chemoradiation. Despite the advances of imaging technology, however, noninvasive staging modalities are still inaccurate in identifying small volume metastatic disease leading potentially to inappropriate treatment and avoidable morbidity in a subgroup of patients. Staging laparoscopy may identify those patients with unsuspected metastatic disease on preoperative imaging and prevent unnecessary laparotomy or chemoradiation. A controversy exists, however, as to whether the procedure should be used routinely or selectively in pancreatic cancer patients with no evidence of metastasis on noninvasive staging. This review aims to assess the current role of staging laparoscopy by examining its diagnostic accuracy and ability to prevent unnecessary treatment as well as its morbidity, oncologic effect and cost-effectiveness. The available literature will be evaluated critically, its limitations identified and exisiting controversies addressed.
Key words: laparoscopy, pancreatic cancer, staging, surgery
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introduction |
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In all, 32 180 new cases of pancreatic adenocarcinoma, equally distributed in both sexes, are estimated to be diagnosed in 2005 in the USA [1
]. While pancreatic cancer ranks tenth among cancers, it is the fourth leading cause of cancer death; the estimated number of cancer deaths in the USA for 2005 is 31 800 [1], indicating that almost all patients with pancreatic cancer die from their disease. Surgery is the only treatment modality that can lead to cure [2, 3]. However, in most series the majority of patients with pancreatic cancer have inoperable disease at presentation; approximately 40–50% have metastatic disease, an additional 40% locally advanced disease and only 10–20% of patients are candidates for curative surgery [3]; indeed, in a recent review of 13 212 patients with pancreatic cancer between 1995 and 2000, 7.5% presented with localized, 29% with regional and 47% with distant disease, and 16% were unstaged [4]. The advanced stage at presentation combined with the aggressiveness of this disease lead to a dismal outcome; the median survival for patients with metastasis is 6 months and for patients with locally advanced disease 10 months [5, 6]. Overall, <5% of patients are alive at 5 years; 15.2% with localized, 6.3% with regional and 1.6% with distant disease [4]. Thus, even after surgical resection only a small number of patients survive long-term.
In a disease with such a poor prognosis even after curative resection, it is not only important to identify those with resectable disease but also to spare patients with incurable disease the morbidity, inconvenience and expense of an unnecessary operation [7, 8]. Accurate staging of patients with pancreatic cancer is therefore very important. Presently, the best initial imaging modality for assessment of patients with suspected pancreatic cancer is a high quality pancreatic computed tomography (CT) scan [9–11]. In a review article published in 2001, high quality CT scan was reported to be highly predictive of pancreatic cancer resectability, with failures occurring in 11–25% of patients [9]. Since that time, however, multiple articles have been published that report a 20–48% unresectability rate in pancreatic cancer patients found to be resectable by latest technology preoperative CT [12–17]. Thus, while CT scan has excellent accuracy (90–100%) in predicting unresectability, it is still limited in its ability to predict resectability [6, 10, 11]. To improve the prediction of resectability, most centers therefore use additional imaging techniques including ultrasound (US), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP) angiogram or positron emission tomography (PET) scan. While this combination of imaging modalities may increase the diagnostic accuracy of preoperative staging, there is still a good proportion of patients with small size metastatic disease (<1 cm) or vascular invasion found at exploration, which preclude curative resection [10, 14–16, 18–20].
In order to minimize the number of patients with imaging occult disease that undergo unnecessary laparotomy, laparoscopy was incorporated early in the staging algorithm of pancreatic cancer patients [21]. Staging laparoscopy has repeatedly been shown to identify small peritoneal or liver implants not seen on preoperative staging [12–17, 19, 20, 22, 23]. On the other hand, the technique is limited in the assessment of vascular invasion by the tumor and deep hepatic metastases; the addition of laparoscopic US and peritoneal cytology to staging laparoscopy appears to improve the diagnostic accuracy of the procedure [20, 23–29].
The current role of laparoscopy in the staging of patients with pancreatic cancer remains controversial, however; while it is clear today that the initial step in the staging algorithm of these patients involves at least one (high quality pancreatic CT scan) or a combination (US, EUS, MRI, ERCP, PET or angiography in addition to CT) of imaging modalities, it is debated whether staging laparoscopy should be offered routinely, selectively or not at all to patients characterized resectable by preoperative imaging [9, 16, 20, 28, 30–33].
This review aims to evaluate the current role of staging laparoscopy and will focus on its diagnostic accuracy and the additive benefit of laparoscopic US and peritoneal cytology. To better assess the value of this invasive procedure we will also review its feasibility, morbidity, oncologic effects and cost effectiveness, and will discuss the limitations of the currently available literature.
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diagnostic accuracy of staging laparoscopy |
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Bernheim in 1911 is credited with the first description of minimally invasive exploration of the abdominal cavity in a patient with pancreatic cancer [34
]. He affirmed that the new technique of ‘organoscopy’ allowed identification of metastasis that had not been detected preoperatively and could save patients an unnecessary laparotomy. The poor technology of that time did not allow the diffusion of the procedure, and it was not until 1978 that Cuschieri et al. [21] published the first series of patients with pancreatic cancer who underwent laparoscopic exploration of their abdomen and described the importance of the technique in identifying patients with unsuspected unresectable disease who could be spared laparotomy. This paper boosted the interest of the surgical community in the procedure and was followed by a large number of publications documenting the value of staging laparoscopy for the assessment of pancreatic cancer patients [12–17, 19, 20, 23]. Studies that have assessed the value of staging laparoscopy belong mainly to one of three categories. Older studies have compared the diagnostic accuracy of staging laparoscopy with that of other imaging modalities; since the role of laparoscopy is to supplement rather than replace other non-invasive imaging modalities, we will not consider such studies in this review. Another group of studies have indirectly assessed the value of laparoscopy by examining the number of unsuspected metastases encountered at open exploration after negative preoperative imaging. Finally, most recent studies, reflecting current practice, have evaluated the role of laparoscopic staging in patients with pancreatic cancer found to be resectable on non-invasive preoperative staging.
indirect assessment
Studies that have assessed the value of laparoscopy indirectly include a report by Friess et al. [35], who found that 30% of 102 pancreatic cancer patients presumed to be resectable based on preoperative imaging had unresectable disease at exploration; 14% due to liver or peritoneal metastases and 17% due to vascular invasion. The authors concluded that only 14% would have benefited from staging laparoscopy assuming that laparoscopy would only have detected visible peritoneal and liver metastases. In another study, Rumstadt et al. [36] reviewed 398 patients who underwent exploratory laparotomy for pancreatic malignancy (except for 12% of patients who had periampullary malignancies) at their institution and concluded that an unnecessary laparotomy could have been avoided by staging laparoscopy in only 29 patients (7%). In the same study, however, only 43% of the patients had curative resections and thus the role of laparoscopy may have been underestimated.
More recently, Maire et al. [15] also assessed indirectly the role of laparoscopy in 69 patients with pancreatic head (84%) and ampullary (16%) cancer. These investigators used high quality CT and EUS to assess resectability and categorized patients in two groups based on resectability probability: a highly likely (n = 56) and an uncertain (n = 13) group. The positive predictive value of the imaging modalities used was found to be 86% for the highly likely resectable group compared with 38% for the uncertain group. The authors argued that 56% of the patients who were found to be unresectable at exploration (n = 16) might have benefited from staging laparoscopy assuming that only peritoneal and liver metastasis would have been reliably detected at laparoscopy; they concluded that staging laparoscopy should be limited to patients with doubtful tumor resectability avoiding unnecessary laparotomy in one fourth of patients [15]. Moreover, Schlieman et al. [37] found that in a group of 89 patients who were believed to have resectable disease after preoperative imaging (high quality pancreatic CT scan) only 45% had resectable disease at exploration; 27% of patients were found to have metastases and an additional 28% had locally advanced disease. In addition, Morganti et al. [14] found the resectability of pancreatic cancer patients to be only 57% after contemporary non-invasive preoperative staging and Ellsmere et al. [12] reported only a 52% resectability rate in patients deemed resectable by multi-detector CT scan.
In our opinion, studies that assess the role of staging laparoscopy indirectly should be interpreted cautiously; apart from the obvious limitation of assessing a procedure that was never performed, all studies assume that staging laparoscopy would have detected only superficial liver and peritoneal metastatic disease neglecting the additional value of laparoscopic US and peritoneal cytology in identifying at least a fraction of patients with locally advanced incurable disease [20, 23, 25–29]. Moreover, it has been suggested that laparoscopy may be more sensitive in detecting very small single metastatic deposits (<3 mm) compared with laparotomy as it allows better, magnified visualization of peritoneal surfaces and especially of the anterior abdominal wall, which is usually poorly seen at laparotomy [38].
direct assessment and the benefit of laparoscopic US
Numerous studies have evaluated the role of staging laparoscopy in pancreatic cancer patients deemed resectable by preoperative imaging. Table 1 summarizes the results of studies that have addressed the effectiveness of staging laparoscopy in identifying patients with unsuspected unresectable disease and in decreasing the number of unnecessary laparotomies. The table lists only studies that used at a minimum high quality pancreatic CT for preoperative staging of all patients and includes only patients considered to be resectable after imaging. In addition, since continuous technological advancements are likely to influence the diagnostic accuracy of preoperative imaging, mainly the most recent articles have been included.
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In a series from the Memorial Sloan-Kettering Cancer Center of 115 patients who were all deemed resectable based on preoperative imaging (all patients had dynamic CT scan, 64% had US, 51% ERCP and 8% mesenteric angiography), laparoscopy identified 41 (36%) patients with unresectable disease who were spared laparotomy. Furthermore, the extended laparoscopy technique that the authors of this study used predicted resectability in 92% of patients [19
]. In another study from the Massachusetts General Hospital that included 125 pancreatic cancer patients who had undergone spiral CT for assessment of resectability, staging laparoscopy identified 31% of patients with unsuspected incurable disease and spared them the morbidity of laparotomy [23]. The sensitivity of staging laparoscopy was calculated at 97% and the specificity at 100%. The authors did not use laparoscopic US and relied solely on preoperative CT to detect vascular invasion, but encountered a 23.3% rate of unresectabilty due to vascular invasion at exploration that was underappreciated by CT. Of note, the high rate of metastasis detection by laparoscopy alone in this study is likely related to the exclusion of stage I patients (tumor <2 cm) and the inclusion of patients with advanced disease (stages II and III). Still, in a study by Kwon et al. [18], staging laparoscopy revealed unsuspected metastasis and changed the surgical approach in 37% of patients with pancreatic cancer (n = 52) despite using CT, MRI, ERCP and angiogram for the preoperative staging of all patients. Thus, even the combination of imaging modalities missed over one-third of patients with unresectable disease.
Further evidence on the value of staging laparoscopy comes from a recent study of 84 patients with resectable pancreatic cancer based on preoperative helical CT scan [38]. In this cohort, staging laparoscopy found unsuspected CT-occult metastases in 31% of patients who were spared laparotomy. The authors employed laparoscopic US in 48 patients and found unsuspected vascular invasion precluding resection and not seen by laparoscopy alone in nine (19%). While the procedure improved resectability by 22% in patients with pancreatic cancer it was also associated with a 16% false-negative rate. In a study from The Netherlands 297 consecutive patients with peripancreatic carcinoma (including pancreatic head, papillary and distal common bile duct tumors) considered to have resectable disease on preoperative imaging (US and helical CT) underwent laparoscopy and laparoscopic US. Laparoscopic staging detected biopsy-proven metastatic disease in 39 patients (13%) and suggested unresectable disease that could not be confirmed by biopsy in another 31 patients (12%), but missed 52 patients (19% false-negative rate) with unresectable disease at exploration; it was also associated with a 4% false-positive rate [16]. The main limitation of this study is the inclusion of patients with primary tumors of variable origin (unspecified numbers of patients with pancreatic head, papillary and distal common bile duct tumors), which have different metastatic behavior and can therefore impact the yield of staging laparoscopy. Similarly, Doran et al. [17] evaluated 190 patients with CT-resectable pancreatic and periampullary tumors with laparoscopy and laparoscopic US and found unresectable disease in 28 (15%). Another 33 patients (16%) were found to be unresectable at exploration and overall 10% of patients were spared laparotomy. The applicability of these results to patients with pancreatic cancer is limited, however, as only 39% of the overall sample (n = 239) had pancreatic ductal adenocarcinoma on histology.
A number of other studies have evaluated the additive benefit of laparoscopic US at the time of laparoscopic staging. In a cohort of 90 patients with pancreatic cancer laparoscopic US helped determine resectability in 13 (14%) where laparoscopic examination alone had lead to equivocal findings [26]. The combined use of laparoscopy and laparoscopic US demonstrated a positive predictive index of 100%, negative predictive index of 98% and accuracy of 98%. Another study that highlighted the value of laparoscopic US revealed that while the combination of laparoscopic US and laparoscopy had an accuracy of 89% in identifying unresectable tumors, laparoscopic US alone was 80% accurate in the identification of tumor size (T stage), 76% for lymph nodes (N stage) and 68% for distant metastasis (M stage), respectively [39]. Moreover, Hunerbein et al. [27] found that laparoscopic US contributed additional information to laparoscopy in 12% of 77 patients with pancreas cancer who were found to have resectable disease on preoperative US, CT and MRI. The combination of staging laparoscopy with US in this study demonstrated unresectability in 57% of patients with a resultant change in surgical management, but the authors did not report the number of patients who were spared laparotomy.
It is evident that laparoscopic staging can identify unsuspected metastases in a significant proportion (15–51%) of patients, leading to fewer unnecessary laparotomies, and is thus a very valuable adjunct in the staging of pancreatic cancer patients. The main controversy today, however, is whether it should be used routinely or selectively in patients with resectable disease on preoperative imaging. Proponents for the routine use of staging laparoscopy cite the high incidence of imaging occult metastatic disease found during laparoscopic examination of the abdominal cavity that leads to avoidance of unnecessary operations and thus benefits patients [20, 30–33]. Proponents for the selective use of staging laparoscopy argue that if high quality imaging is used only a small percentage of patients benefit from staging laparoscopy and the procedure is not cost-effective [9, 16, 40]; a review by Pisters et al. [9] concluded that if staging laparoscopy is performed routinely on patients judged to have resectable disease by high-quality CT, only 4–13% of patients would be spared an unnecessary laparotomy. This conclusion was based, however, mainly on studies that assessed the role of staging laparoscopy indirectly, which have a number of limitations, as discussed earlier. Nevertheless, as a result of this important criticism for the routine use of staging laparoscopy, recent studies have attempted to identify preoperative variables that could enhance the yield of laparoscopic staging.
Morganti et al. [14] evaluated the prognostic effect of clinical staging in pancreatic adenocarcinoma by comparing preoperative staging using ERCP, CT scan and US (clinical staging) with surgical/pathological staging. In their analysis of 54 patients they found that 33% of patients had been understaged and 4% overstaged by clinical staging. The sensitivity, specificity, positive predictive value and negative predictive value of the combined imaging modalities for tumor size (vascular involvement) were 74%, 96%, 94% and 81%, respectively, whereas for nodal status assessment they were 64%, 95%, 93% and 72%, respectively. Moreover, they found that patients with tumor size >3 cm on preoperative imaging had significantly more unsuspected metastases at exploration compared with those with tumors <3 cm (22% versus 0%, respectively; P < 0.01) and shorter median (8 versus 17 months) and 5-year survival (0% versus 15.5%; P < 0.01). Based on these findings the authors suggested that the size of the tumor on preoperative imaging might be an effective way to select patients for staging laparoscopy, since all patients who were found to have occult metastatic disease at laparotomy had tumors >3 cm [14]. Further supporting evidence comes from a study of 45 patients with resectable pancreatic cancer on preoperative CT scan; patients who were found to be resectable at exploration had a mean tumor size of 3.1 cm on CT scan compared with 4.4 cm in patients with metastatic disease (P < 0.005) [13].
In another study, Schlieman et al. [37] evaluated the utility of preoperative tumor markers in determining resectability of pancreatic cancer in 89 patients; patients with resectable disease at exploration had a median CA 19-9 preoperative level of 73.5 U/ml, whereas those with unresectable disease had a median level of 374 U/ml (P < 0.001). The authors calculated that a CA 19-9 level >150 U/ml had a positive predictive value of 88% in identifying unresectability in patients believed to be resectable according to preoperative imaging and concluded that this subgroup might benefit the most from staging laparoscopy [37]. Further support for the utility of serum CA19-9 in improving the effectiveness of staging laparoscopy comes from another recent study; Connor et al. [41] studied 159 patients between 1997–2004 who had resectable pancreatic cancer by CT and had undergone staging laparoscopy. They found that a preoperative CA19-9 level 
150 kU/l had a positive predictive value of 95% in predicting resectability at laparoscopic assessment. Furthermore, the authors suggested that by adjusting this CA 19-9 level to the presence of jaundice the yield of staging laparoscopy could have been increased from 15% to 25%, and the procedure avoided in 55% of patients.
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the role of peritoneal cytology |
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In a pioneer report from 1991, Warshaw [42
] studied the ascites and peritoneal washings of 40 patients with localized, histologically proven pancreatic cancer. He found free intraperitoneal cancer cells in 50% of patients with small amounts of ascites and in 25% of those without ascites, and documented worse resectability rates and survival in patients with positive peritoneal cytology. A number of studies have addressed the role of peritoneal washings in the staging of pancreatic cancer patients since then [22, 23, 28, 29, 43–46]; Merchant et al. [43] found a positive predictive value of 94%, a specificity of 98% but a sensitivity of only 25% for positive peritoneal cytology in determining unresectability of pancreatic cancer patients. On the other hand, more recently, Schmidt et al. [46] found a sensitivity of 100% and specificity of 96% for positive peritoneal cytology in the presence of a disrupted ventral pancreatic margin (when peripancreatic fatty tissue could not be differentiated from the tumor by helical CT scan) as predictor of unresectability. Importantly, Jimenez et al. [23] reported a 7% rate of positive peritoneal cytology as the only evidence of metastatic disease during laparoscopy in 125 patients deemed resectable by preoperative spiral CT scan; the same authors reported a 14% rate of positive peritoneal cytology in the absence of visible metastasis in a larger number of patients (n = 239) from their institution [28]. In addition, Liu and Traverso [22] documented a 12% rate of positive peritoneal cytology as the only evidence of metastatic disease during laparoscopy in patients with locally advanced pancreatic cancer but no evidence of distant disease on helical CT scan. In contrast, Nieveen van Dijkum et al. [47] found that only seven out of 236 (3%) patients with periampullary tumors had cancer cells on peritoneal cytology performed during staging laparoscopy, and most of them had other evidence of unresectability. The authors concluded that owing to its low yield, cytology of peritoneal lavage should no longer be performed during staging laparoscopy.
The wide reported range (3–53%) of positive peritoneal lavage in pancreatic cancer patients may reflect differences in the studied populations; patients with localized disease have fewer positive results compared with those with locally advanced or metastatic disease [30]. Furthermore, a higher rate of positive washings has been observed in patients with larger size cancers or cancers of the pancreatic body or tail [6, 28]. Nevertheless, it appears that a small but important number of patients with resectable pancreatic cancer may be spared an unnecessary laparotomy by the addition of peritoneal cytology to staging laparoscopy. Moreover, most studies suggest that pancreatic cancer patients with positive peritoneal cytology have similar outcomes to patients with metastatic disease; this is reflected in the sixth edition of the American Joint Commission on Cancer (AJCC) Cancer Staging Manual, which designates positive peritoneal cytology as M1 disease [48].
It should be noted that the procedure may prolong the duration of staging laparoscopy significantly, especially if the cytology results are to be awaited to determine whether curative resection can be performed in the same setting. In addition, the cost-effectiveness of peritoneal cytology is unknown.
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impact of tumor location |
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The location of the primary lesion appears to influence the yield of staging laparoscopy. Barreiro et al. [49
] examined the value of staging laparoscopy in relation to tumor location; in their study, unnecessary laparotomy was avoided in 35% of patients with pancreatic cancer but only in 2.3% of patients with non-pancreatic periampullary tumors. In another study, staging laparoscopy identified unresectable disease in 10% of 144 patients with non-pancreatic periampullary tumors, and only one-third of those patients were spared laparotomy [50]. Furthermore, Vollmer et al. [38] did not gain any additional information by applying staging laparoscopy to patients with periampullary cancers. Although many studies evaluating the usefulness of staging laparoscopy have not distinguished between cancers of the pancreas and non-pancreatic periampullary tumors, despite the better outcome observed in the latter group, it is evident from the above studies that the yield of staging laparoscopy for non-pancreatic periampullary tumors is very low and its routine use probably not indicated [38, 49, 50].
Besides these differences between pancreatic and periampullary tumors, even the location of the tumor within the pancreas appears to be related to the yield of staging laparoscopy, as lesions of the pancreatic body and tail have been associated with a higher rate of intraperitoneal metastasis, presumably because of their advanced size at the time of diagnosis. At least two studies document this; Liu and Traverso [22] found that tumors of the pancreatic body and tail were twice as likely to have unsuspected metastasis at laparoscopy compared with pancreatic head tumors (53% versus 28%, respectively). Similarly, Jimenez et al. [23] reported unsuspected metastases at staging laparoscopy in 17% of patients with pancreatic head tumors compared with 36% of patients with body and tail tumors (P = 0.02).
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staging laparoscopy for locally advanced disease |
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Patients with locally advanced disease (unresectable) but no evidence of distant metastasis comprise about 40% of pancreatic cancer patients (the new AJCC staging system has reclassified these patients from stage IVA to stage III [48
]). The current treatment of these patients involves radiation-based protocols aiming at locoregional control; the Gastrointestinal Tumor Study Group reported that the combination of bolus 5-FU and external beam radiation doubled the median survival of this patient population [51]. Furthermore, several centers have used neo-adjuvant chemotherapy to induce tumor regression in this patient population [22, 52]; in a study by White et al. [52], 19% of patients with locally advanced disease were downstaged by neo-adjuvant treatment and 80% of those underwent curative resections with outcome equal to patients with localized disease. Hence, patients with locally advanced pancreatic cancer have distinct treatment options and outcome compared with patients with metastatic disease. Given the limitations of the current imaging modalities in detecting small peritoneal or liver metastasis [10, 11] and the fact that locally advanced pancreatic tumors are more likely to be associated with such metastases [30], it appears that some patients with locally advanced disease are being understaged and therefore receive inappropriate treatment; if patients with imaging-occult stage IV disease are treated as stage III patients, not only will they not benefit from treatment but they will also be exposed to unnecessary treatment-related morbidity. In addition, unnecessary cost will be added to the health-care system and studies that evaluate the effectiveness of such treatment protocols will erroneously document inferior outcomes. Thus, diagnostic laparoscopy may play an important role in appropriately selecting those patients with true locally advanced disease and excluding patients with CT-occult metastatic disease from further treatment and unnecessary morbidity [22, 30, 53].
Liu and Traverso [22] recently published their experience with laparoscopic staging of 70 patients with locally advanced pancreatic cancer; they found that 34% of those patients had CT-occult stage IV disease (including peritoneal and liver implants or positive peritoneal lavage) and that patients with body and tail tumors were twice as likely to have unsuspected metastasis compared with tumors of the head. Furthermore, in a prospective study of 100 patients with locally advanced pancreatic cancer, Shoup et al. [53] found that staging laparoscopy identified metastatic disease in 37% of patients that was not seen on preoperative imaging (high quality CT scan or MRI); the authors concluded that patients considered for treatment protocols for locally unresectable pancreatic cancer should be staged laparoscopically before initiation of therapy.
In addition to improving identification of stage IV disease, diagnostic laparoscopy has also been shown to be associated with increased utilization of adjuvant treatment in patients with unresectable intra-abdominal malignancies compared with exploratory laparotomy; in a study of 79 patients Velanovich et al. [54] found that 76% of patients with unresectable disease at staging laparoscopy received postoperative chemotherapy, radiation therapy or both, compared with only 43% of patients with findings of unresectability at exploratory laparotomy (P < 0.01). Moreover, the median number of days from surgery to postoperative cancer treatment was significantly shorter in the staging laparoscopy group (13 versus 35 days; P < 0.001) [54], with a few patients starting treatment before hospital discharge. Even though this study included patients with various intraabdominal malignancies, the majority of patients had metastatic pancreatic cancer and is thus relevant to this review. Importantly, this study emphasizes the value of staging laparoscopy in preventing a delay of primary treatment (chemotherapy or chemoradiation) in the subset of patients who are found to be unresectable by avoiding laparotomy and its associated longer convalescence period.
Another argument of the opponents of staging laparoscopy is that its usefulness is limited because inoperable patients can benefit from biliary and gastric bypass performed during open exploration. Evidence is accumulating, however, that the number of patients requiring a biliary or gastric bypass procedure may not be as high as initially assumed [55]; Espat et al. [56] followed 115 patients with pancreatic cancer who were found to be unresectable during staging laparoscopy and had no drainage procedure performed. In this cohort, patients with metastatic disease had a median survival of 6.2 months and those with locally advanced disease 7.8 months, respectively. During their follow-up period only three (2%) patients required an open surgical procedure for the treatment of biliary or gastric obstruction. Furthermore, both gastric and biliary bypass can be performed laparoscopically with minimal morbidity [57] and recent endoscopic advances make the relief of biliary or gastric outlet obstruction possible without the need for an operation. Hindmarsh et al. [58] reported their preliminary results on 26 patients with malignant gastric outlet obstruction who were randomized to undergo laparoscopic bypass versus duodenal stenting. Compared with gastrojejunostomy, duodenal stenting was associated with fewer complications (78% versus 8%, respectively; P < 0.01), shorter hospital stay (11 versus 4 days, respectively; P = 0.02) and lower pain scores on postoperative day 1 (4.4 versus 2.7 on visual analog scale, respectively; P = not significant) [58]. Although good long-term patency in the face of minimal morbidity of stents placed for colorectal malignancies has been reported [59], more experience with duodenal stents is needed to better assess this nonoperative modality. On the other hand, Nieveen van Dijkum et al. [16] randomized 27 patients with unresectable peripancreatic malignancies into a group of endoscopic palliation and a group of surgical palliation. While the small sample size of this study did not allow the detection of statistical significant differences in the outcome of the two groups, it revealed a clear tendency towards a decreased procedure-related hospital stay (3 versus 12 days, respectively) for the endoscopic palliation group but an improved average survival (116 versus 192 days, respectively) and hospital-free survival (99 versus 154 days, respectively) for the surgical palliation group [16].
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technique and feasibility of the procedure |
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The procedure for staging laparoscopy and its variations are well described in the literature [6
, 18, 19, 23, 31, 60]. In particular, under general anesthesia and following the establishment of pneumoperitoneum, a thorough evaluation of peritoneal surfaces is performed; the suprahepatic and infrahepatic spaces, the surface of the bowel, the lesser sac, the root of the transverse mesocolon and small bowel, the ligament of Treitz, the paracolic gutters and pelvis are inspected with frequent bed position changes as necessary [6]. In addition to visual inspection, peritoneal washings can be performed, ascitic fluid if present sent for cytology and biopsies of any suspicious lesions obtained. If no metastatic disease is identified on inspection, a detailed laparoscopic US examination can be employed; the deep hepatic parenchyma, the portal vein, mesenteric vessels, celiac trunk, hepatic artery, the entire pancreas and even pathologic periportal and paraaortic nodes can be evaluated and biopsied if indicated. The addition of color flow Doppler can further assist in the assessment of vascular patency.
A controversy exists in the literature about the extent of staging laparoscopy between advocates of a short duration procedure that is based only on inspection of surfaces [8, 13, 23], and those who believe that a more extensive procedure that includes opening of the lesser sac and assessment of the vessels is in order [20, 25–27, 61]. Advantages of a limited examination include that it can be performed quickly (usually within 10–20 min), can be done through one port, does not require significant expertise, minimizes the risk of potential complications by dissection near vascular structures and has good diagnostic accuracy [23]. On the other hand, the extended technique may detect vascular invasion and deep hepatic metastasis, which are often missed by visual inspection alone, and thus improve the diagnostic accuracy of staging laparoscopy. Furthermore, most studies document that it can be performed safely without a significant increase in morbidity and within a reasonable amount of time. It should be noted that differences in the technique of staging laparoscopy are likely to influence the yield of the procedure and should be taken into consideration when evaluating related reports.
With regards to the feasibility of staging laparoscopy most studies report success rates in the high 90%s (see Table 2). Dense adhesions that impair inspection and examination with the US probe are the main reason for technical failures. Nevertheless, even patients with adhesions can be examined, but the extent and yield of the examination may be compromised.
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morbidity and mortality |
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To assess accurately the value of staging laparoscopy in the management of patients with pancreatic cancer, in addition to its diagnostic accuracy, the morbidity and potential mortality of this invasive procedure need to be evaluated. Moreover, the morbidity of staging laparoscopy has to compare favorably with that of open exploration to justify its use. It is well documented today that laparoscopy, apart from its cosmetic advantage, benefits patients by decreasing postoperative pain, hospital stay and recovery duration [62
–65], and in many cases morbidity compared with open surgery [63–65]. Does staging laparoscopy confer the same advantages to patients with pancreatic cancer when compared with open exploration?
Initial evidence comes from the field of trauma; Sosa et al. [66] retrospectively reviewed the morbidity and hospital stay of 817 patients with abdominal gunshot wounds over a 4-year period and identified patients who had a negative exploration but no other concomitant procedures. The authors compared 34 patients who had undergone a negative diagnostic laparoscopy to 69 patients who had a negative exploratory laparotomy and found that laparoscopy was associated with a significantly lower morbidity and hospital stay (3% versus 22% and 1.4 versus 5.1 days, respectively; P < 0.01). While this study describes a population without cancer, it convincingly demonstrates the superiority of laparoscopic over open exploration of the abdominal cavity in the absence of other concurrent procedures.
In pancreatic cancer patients comparative data between staging laparoscopy and laparotomy are very limited. In their series, Conlon et al. [19] reported a 0% morbidity and mortality for staging laparoscopy and showed that patients who underwent this procedure had significantly shorter hospital stays compared with those who had open exploration (a median of 2 versus 7 days, respectively; P < 0.01); unfortunately, morbidity comparisons can not be made because the authors did not report the morbidity of open exploration. In another study, the hospital stay of patients with advanced pancreatic cancer who were palliated laparoscopically was significantly shorter compared with patients who were palliated by open surgery (3.7 ± 1.5 versus 10.3 ± 2.6 days, respectively; P < 0.001), but the morbidity was similar [67].
On the other hand, morbidity and mortality data of laparoscopic staging alone is more abundant (Table 2). In an article by Hunerbein et al. [27], the morbidity associated with the procedure in a large sample of patients (n = 668) was 3.1%; minor complications accounted for the majority of this morbidity and included wound infections, bleeding at port sites or skin emphysema, but two patients (0.3%) suffered a myocardial infarction and a pulmonary embolism, respectively. In addition, four patients (0.6%) had to be converted for the repair of intraoperative inadvertent intestinal or vascular injuries and another five due to inability to perform a complete laparoscopic examination secondary to adhesions (overall conversion rate of 1.3%), and no port metastases were noted. In this large series of patients, one death (0.15%) was encountered due to sepsis from a colonic perforation that was missed during laparoscopy. This study documents effectively the low morbidity and mortality of staging laparoscopy even though it included only a small percentage (11.5%) of patients with pancreatic cancer.
In another large cohort study of 420 patients, Nieveen van Dijkum et al. [68] reported the morbidity and mortality associated with staging laparoscopy and laparoscopic US; similar to the previously mentioned study by Hunerbein et al. [27], this study included patients with a variety of intraabdominal malignancies and was associated with a morbidity of 4% (3% minor and 1% major) and no mortality. Of note, a 2% rate of port-site metastases was observed which occurred always in patients with advanced disease [68].
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oncologic effect |
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Laparoscopy was embraced enthusiastically by surgeons for the treatment of cancer patients early after its introduction into clinical practice in the late 1980s to early 1990s. Initial reports of a significant number of port-site recurrences in cancer patients (up to 21%) [69
], however, led to skepticism and dissipation of this early enthusiasm and fostered research efforts to better define the oncogenic effects of the procedure. It is well documented today, that the CO2 pneumoperitoneum can accelerate cancer cell growth in vitro [70, 71], but its effect appears to be of importance only for very high/supraphysiologic tumor inoculums (>106) [72]. The initially reported high incidence of port-site recurrences after laparoscopy has been attributed to incorrect surgical technique [72]; Schneider et al. [73] demonstrated in an experimental model that port site recurrences could be significantly reduced by employing appropriate techniques including trocar fixation, prevention of gas leaks, rinsing of instruments, trocars and wounds with povidone-iodine, protection of specimen extraction sites, and peritoneal closure.
The best clinical evidence on the oncogenic effect of laparoscopy can be found in the colorectal cancer literature. Multiple randomized trials on laparoscopic colectomies for cancer document wound recurrences in fewer than 1% of patients [62,74]; the most recent level I evidence comes from the COST trial, which documented a long-term port-site recurrence rate of 0.5% in 435 patients who underwent laparoscopic colectomy that was comparable to a 0.2% incidence after open colectomy in 428 patients (P = not significant) [62]. The same study proved that laparoscopic colon resection lead to equivalent recurrence rates and overall survival at 3 years follow-up compared with open resection. Nonetheless, another randomized controlled study from Spain demonstrated a survival advantage for stage III colon cancer patients after laparoscopic colectomy compared with open resection [74], but these results have yet to be reproduced.
In concurrence with the colorectal cancer literature, the majority of studies on staging laparoscopy have reported a 0–2% incidence of port-site recurrences [68, 75–77]. In a study of 235 patients who had undergone exploratory laparotomy or staging laparoscopy, laparoscopy was not associated with increased port-site recurrences or peritoneal disease progression [77]. Importantly, most port-site recurrences appear to occur in patients with advanced disease, especially those with extensive peritoneal carcinomatosis [68, 75]. This was demonstrated nicely in a large prospective study of 533 patients with intra-abdominal malignancies; following staging laparoscopy port-site recurrences occurred in four patients (0.8%). When patients were grouped according to disease extent, three of the recurrences occurred in 71 patients with advanced disease (4.2%) compared with only one recurrence in 462 patients without advanced disease (0.2%; P < 0.003) [76].
Furthermore, in a population-based study from the SEER database, patients with pancreatic cancer >65 years old were identified and their survival assessed according to surgical treatment received; 112 patients who had undergone only a laparoscopic procedure had a median survival of 4.8 compared with 5.3 months of 791 patients who were treated with open surgery (P = 0.83). Even after adjustment for age, sex, tumor stage and surgical or adjuvant treatment received, no outcome differences between the two groups could be shown [78].
These studies lend support to the conclusion that staging laparoscopy does not adversely affect outcome of pancreatic cancer patients and is associated with a very small risk of port-site recurrences if appropriate technique is used.
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cost-effectiveness |
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Cost effectiveness data on staging laparoscopy are limited. Andren-Sandberg et al. [79
] found that patients who underwent staging laparoscopy had a 31% lower total hospital cost compared with those who had laparotomy after laparoscopic staging, mainly due to shorter hospital stays in the laparoscopy group. Furthermore, Holzman et al. [67] found that in patients with unresectable pancreatic cancer who had a palliative procedure performed at the time of staging laparoscopy the overall cost was significantly lower compared with patients who were palliated at the time of open exploration ($9700 versus $14 800; P < 0.01) albeit at the expense of a higher cost for converted procedures ($20 100); the lower cost of laparoscopically treated patients was also a consequence of decreased hospital stay.
In contrast, Friess et al. [35] concluded that staging laparoscopy had to be seven times cheaper compared with exploratory laparotomy to achieve a cost benefit. The authors based their conclusion on the finding of 14% liver and peritoneal metastasis during laparotomy in 119 patients with pancreatic cancer who had been deemed resectable by preoperative imaging. Patients who were unresectable due to unsuspected retroperitoneal tumor infiltration (17%) were not considered in their analysis, however.
Obertop and Gouma [80] used a cost utility analysis to examine which management strategy for pancreatic cancer patients would be the most cost-effective; based on the available literature they compared a ‘non-surgical’ strategy, consisting of ERCP with biliary stent placement and staging laparoscopy followed by laparotomy if needed, with a ‘surgical’ strategy, comprised of immediate exploratory laparotomy, in patients who were found to have resectable disease on preoperative spiral CT scan. The authors concluded that if the yield of staging laparoscopy is high (at least 30%) the ‘non-surgical’ strategy would be more cost-effective [80].
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limitations of available literature |
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The literature on staging laparoscopy has many limitations; there is no level I evidence available as no randomized controlled trials have been published on the subject to allow firm conclusions to be drawn. In addition, population-based data are very limited as the majority of studies are single institution reports from highly specialized centers, making generalizations difficult and allowing institutional and personal biases to be introduced into the results.
Furthermore, the available data are not uniform across studies, making their analysis difficult. A number of studies assess the role of laparoscopy indirectly without having even a single laparoscopic staging procedure ever performed (referred to as ‘phantom’ studies by some authors) [17] and assume that only visible metastatic disease would have been detected at the time of laparoscopy, ignoring the value of laparoscopic US and cytology. Other studies do not report clearly the quality of preoperative imaging, the criteria used to define resectability and the number of R0 resections [9]. Importantly, studies often evaluate unhomogeneous patient samples, including patients with localized and locally advanced pancreatic cancers, with periampullary and other non-pancreatic cancers or even with benign disease without reporting results separately. Moreover, the information on the cost-effectiveness of the procedure is extremely limited and there are no studies to our knowledge that assess the quality of life of patients undergoing staging laparoscopy versus those undergoing open exploration.
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summary |
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The role of laparoscopy in the staging of pancreatic cancer patients remains controversial; while it is generally agreed that the initial step in the staging algorithm of these patients should involve non-invasive imaging modalities, it is debated whether staging laparoscopy should be offered routinely, selectively or not at all to those patients deemed resectable in their preoperative work-up.
Despite the technological advances of imaging modalities, however, recent series continue to document a high incidence (20–57%) of unresectability found at the time of surgery. Low volume metastatic disease and retroperitoneal vascular invasion precluding curative resection are the main reasons for the failure of non-invasive imaging in predicting resectability. The role of laparoscopic staging is in identifying those patients with imaging occult unresectable disease and thus in preventing the morbidity of unnecessary laparotomies; the reviewed literature suggests that 10–36% of patients can be spared an unnecessary laparotomy.
Staging laparoscopy can be performed successfully in the vast majority of patients and is associated with minimal morbidity (0–4%) and faster recovery compared with open exploration. In addition, the procedure does not influence negatively the oncologic outcome of pancreatic cancer patients and, if an appropriate technique is used, wound recurrences are very uncommon (<1%).
Laparoscopic US and to a lesser extent peritoneal cytology, performed at the time of staging laparoscopy, improve its diagnostic accuracy by allowing the identification of unresectable disease (deep hepatic metastases or vascular invasion) missed by visual inspection alone. On the other hand, laparoscopic US and peritoneal cytology increase the duration and cost of a procedure the cost-effectiveness of which is already being questioned.
While staging laparoscopy is clearly beneficial for a proportion of patients with pancreatic cancer and indicated in all patients with equivocal findings on preoperative imaging, it does not affect the management of the majority of patients examined. The selective use of staging laparoscopy may therefore be more appropriate provided accurate predictors can be identified that will increase its yield. Predictors identified in this review include large tumor size (>3 cm), tumor location in the body or tail of the pancreas, or a CA19-9 level >150 U/ml. However, until studies are available that validate prospectively such preoperative predictors, the routine application of staging laparoscopy in patients deemed resectable by preoperative imaging may be still justified.
Nonetheless, an emerging indication for staging laparoscopy is in patients with locally advanced pancreatic cancer and no evidence of distant disease who are considered for chemoradiation. In this patient subgroup, staging laparoscopy may effectively identify imaging-occult stage IV disease and prevent the morbidity and cost associated with unnecessary treatment. In addition, by allowing better selection of treatment candidates it may improve the results of adjuvant protocols.
In conclusion, staging laparoscopy has an important role in the staging algorithm of pancreatic cancer patients and will likely continue to be a valuable tool in the surgeon's armamentarium despite expected improvements in imaging modalities. The available literature should be interpreted carefully, however, as it has many limitations. High quality, multi-institutional, well-designed studies are needed to help clarify many of the existing controversies.
Received for publication May 5, 2005. Revision received August 1, 2005. Accepted for publication August 2, 2005.
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