Controversies in the Surgical Management of Cholangiocarcinoma and Gallbladder Cancer

Controversies in the Surgical Management of Cholangiocarcinoma and Gallbladder Cancer Jason K. Sicklick and Michael A. Choti Cholangiocarcinoma and gallbladder cancer are relatively rare malignancies with poor prognoses. Surgery is the primary form of treatment, with few data being available on the use of adjuvant therapies. Even with regard to surgery, there are few definitive data supporting various approaches that nevertheless are widely used and have become recognized as traditional. This review examines available information and controversies in the areas of preoperative evaluation and surgical treatment of cholangiocarcinoma and gallbladder cancer. Semin Oncol 32(suppl 9):S112-S117 © 2005 Elsevier Inc. All rights reserved.

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ile duct and gallbladder cancers (GBCA) are rare malignancies with classically poor prognoses, and presentation is more common in advanced stages of disease. Because of the infrequency of these malignancies as compared with other gastrointestinal cancers, there are less data and fewer randomized clinical trials in the literature regarding management. Several aspects of practice and treatment are solely based on small, retrospective case series and/or individual institutional experiences. As a result, both of these cancer types are shrouded in significant controversies regarding management. Despite the debate, clearly these diseases are distinct and should be managed differently. The following review will outline selection of appropriate surgical candidates and discuss the controversies in the preoperative, intraoperative, and postoperative management of patients with cholangiocarcinoma (CC) and GBCA. Both cancer types are more common outside the United States, with particularly higher incidences in South America, Central-Eastern Europe, Israel, and northern Japan. In the United States, GBCA has an incidence of 1.7 per 100,000 in females and 0.9 per 100,000 in males; over 80% of these tumors are adenocarcinomas. Of GBCA cases, approximately 10% are incidental diagnoses noted on histopathologic review of laparoscopic cholecystectomy specimens.1 In contrast, CC has a similar incidence to GBCA, but is more common in males than in females, with an incidence of 1.5 and 1.0 per 100,000, respectively. Bile duct adenocarcinomas also occur in two distinct anatomic and incidence patterns Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD. Dr Choti has no significant financial relationships to disclose. Address reprint requests to Michael A. Choti, MD, Johns Hopkins Hospital, 600 N Wolfe St, Halsted 614, Baltimore, MD 21287-5614; E-mail: [email protected]

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0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.04.018

described as the intrahepatic (or peripheral) cholangiocarcinoma (ICC; 6%) and the extrahepatic cholangiocarcinoma, which includes the hilar-perihilar (67%) and distal peri-pancreatic tumors (27%).2 Of these subtypes, the hilar cholangiocarcinoma (HICC), a Klatskin’s tumor, is the most common. In general, the surgical management of ICC is very similar to that of other primary intrahepatic malignancies such as hepatocellular carcinoma. Similarly, the distal peripancreatic tumors are managed in a similar manner to pancreatic head tumors. In this review, we will primarily focus on the management of GBCA, as well as hilar-perihilar disease, because it is the most common but also the most controversial.1,3

Controversies in the Management of Hilar Cholangiocarcinoma Given that resection is the only potential cure for HICC, surgical management hinges on whether the disease is completely resectable or not. Similar to the management of other upper gastrointestinal malignancies, appropriate patient selection is critical. The criteria for unresectability may be categorized according to patient-related, local tumor, and metastatic disease factors (Table 1).4,5 In the ultimate decision on resectability, difficulty often arises in determining which points apply.6 As a result, three major divisive issues have arisen in the current management of HICC to appropriately select patients and surgically achieve this goal. What Preoperative Studies are Required for Evaluation? In the initial selection of patients, there is disagreement about the preoperative evaluation of HICC. It is undisputed, how-

Cholangiocarcinoma and gallbladder cancer Table 1 Determining Resectability for Hilar Cholangiocarcinoma Factors

Reasons for Unresectability

Patient-related 1. Cirrhosis 2. Insufficient remnant liver volume to maintain adequate hepatic function (ie, less than 30% remaining volume) 3. Medical contraindications to major abdominal surgery Local tumor- 1. Bilateral tumor extension into secondary related bile ducts (relative contraindication) 2. Encasement or occlusion of the main portal vein proximal to its bifurcation (relative contraindication). May resect in selected cases without complete involvement 3. Unilateral tumor extension into secondary bile ducts with contralateral vascular encasement or occlusion 4. Atrophy of one hepatic lobe with contralateral portal vein encasement 5. Atrophy of one hepatic lobe with contralateral secondary biliary extension Metastatic 1. N1 lymphadenopathy with regional disease lymph node metastases (hilar, celiac, periduodenal, peripancreatic, and superior mesenteric) 2. Any distant metastases including even a solitary liver metastasis

ever, that the extent of bile duct involvement must be determined. This is typically accomplished with endoscopic retrograde cholangiopancreatography, or more recently, with magnetic resonance cholangiopancreatography, because it is a sensitive and specific, noninvasive option.7,8 Occasionally, a patient may undergo percutaneous transhepatic cholangiography (PTC) for evaluation.9,10 In conjunction, either computerized tomography or magnetic resonance imaging may provide additional necessary information that cannot be seen with cholangiography. Cross-sectional imaging allows assessment of soft-tissue extension, lymphatic involvement, vascular involvement, hepatic lobar atrophy, remnant liver volume, and evidence of metastatic disease. Therefore, each patient must at least undergo one form of cholangiography and cross-sectional imaging. How invasive this work-up should be remains up for debate. Is Preoperative Biliary Stenting Necessary? In the setting of HICC, there are very limited data in the literature on preoperative biliary stenting. It is often the philosophy of a surgeon or institution that guides whether to stent (or not). At our institution, we often favor preoperative stenting in patients with HICC at least on the contralateral side. PTC has several advantages including improved preoperative assessment of resectability because of the ability to perform blind biopsies up the duct to better stage the extent of biliary tract disease, and the ability to preoperatively correct a patient’s hyperbilirubinemia. PTC may also facilitate intraoperative biliary identification and reconstruction, as

S113 well as reduce the rate of postoperative biliary complications. Some clinicians believe that it is unnecessary for assessment, particularly in the era of magnetic resonance cholangiopancreatography.10,11 Similarly, some argue that the risks and cost of the procedure are real, and moreover, that stenting may increase postoperative complication rates, especially the rate of biliary sepsis.11 Yet, others argue that PTC may not significantly facilitate the identification of the bile duct intraoperatively. And therefore, some centers use it routinely—as we do, others use it selectively, and still others avoid it if at all possible. How Extensive of a Surgical Resection is Required? Routine Hepatectomy with Caudate Lobe Resection. According to the Bismuth-Corlette classification of perihilar CCs, some cases of HICC involve the common bile duct (CBD) or the confluence of the right and left hepatic ducts.12 Type IV tumors with bilateral extensive ductal involvement are unresectable, and are associated with poor survival rates. In contrast, type IIIA or IIIB tumors have unilateral involvement of the CBD and right or left hepatic duct, respectively. Universally, these require an ipsilateral hepatectomy along with an extrahepatic biliary resection (Table 2). Several case series have shown that the R0 resection rate is increased in series that have higher percentages of liver resections.13 Moreover, recent reports have shown that improved R0 resection rates are associated with improved survival rates.14,15 Clearly, tumor resection with negative margins is essential for providing a curative benefit. The issue is how best to accomplish this. Controversy begins to arise when discussing whether routine hepatectomy with caudate lobe resection should be performed because these tumors often extend into one lobe as well as into the caudate lobe. In one Japanese-American study, additional caudate lobectomy contributed to a higher margin-negative resection rate in the Nagoya cohort where 89% of patients underwent additional en bloc resection.5 We would argue that this radical resection is appropriate in properly selected patients. Portal Lymphadenectomy. With the greater trend toward routine hepatectomy, there has been a rise in portal lymphadenectomy. Although the data proving the survival benefit of radical lymph node dissection is less clear than that of hepatic resection, it has gained popularity.13 However, in the

Table 2 Surgical Management of Hilar Cholangiocarcinoma Management Historically accepted

Recently accepted

Controversial

Extent of Resection Excision of supraduodenal biliary tract Cholecystectomy Restoration of biliary-enteric continuity Routine hepatectomy with caudate lobe resection Portal lymphadenectomy Selective major vascular resection Routine portal vein resection

J.K. Sicklick and M.A. Choti

S114 course of performing a biliary resection, a concomitant lymphadenectomy is a reasonable option.

Table 3 Determining Resectability for Gallbladder Cancer

Major Vascular Resection. Although surgeons began performing hepatic artery resections for the treatment of biliary tract cancer approximately one decade ago, the indications and the benefits remain nebulous. In a Japanese study by Shimada et al,16 who evaluated patients with HICC and GBCA, 10 of the 26 patients with HICC (38%) and 5 of the 13 patients with GBCA (38%) underwent vascular resection including 9 portal vein and 12 hepatic artery resections. Six of these patients with HICC underwent both arterial and venous resections. The postoperative patency rates were 88.0% and 83.3% for portal vein and hepatic artery reconstructions, respectively. However, these procedures are not without complications that include liver failure secondary to portal thrombus, and liver abscesses caused by arterial obstruction. The mortality in this study increased with vascular reconstruction (13.3% v 8.3%). In a separate prospective study of surgical treatment of HICC by Kondo et al,17 40 of 42 patients that were explored underwent resection. However, in those patients that underwent hepatic-artery or portal-vein resection, there was similar survival compared with those that did not undergo these procedures. Furthermore, univariate analysis indicated that concomitant hepatic artery resection was a significant prognostic factor for a decreased median survival. This may be because of an attempt at resecting more advanced disease, peritoneal seeding leading to earlier recurrence, or perioperative complications. Therefore, current data suggests a limited role for arterial or portal venous resection, except in selected cases being performed by experienced surgeons with microvascular expertise. However, as noted above, many liver centers will proceed with major vascular resection in cases involving the portal vein. Some groups, particularly those in Berlin, Germany, have supported a strategy of routine portal vein resection for all HICCs.15,18-20 Neuhaus et al15 reported up to a 72% 5-year survival rate following trisegmentectomy with concomitant resection of the portal vein bifurcation in 133 patients. Their data may suggest possible improved survival rates because of the adjacency of the portal vein to the primary tumor. On the other hand, the Japanese data suggest there is no difference in median survival between patients with portal vein invasion or resection.17 Others have suggested a higher mortality with major resection.14,17,21 Considering that many institutions are unable to attain the benefits reported by the German surgeons, evidence for selected arterial, venous, or combined resection remains limited, and routine portal venous resection does not appear to be suited for general application.

Patient-related

Controversies in the Management of GBCA GBCA is distinct from CC and thus has three different surgical controversies enveloping it in settings of preoperative evaluation and surgical management. It is recognized that the extent of tumor invasion has a significant role in the operative management of GBCA. Therefore, like HICC, the difficulty in

Factors

Local tumor-related

Metastatic disease

Reasons for Unresectability 1. Cirrhosis 2. Insufficient remnant liver volume to maintain adequate hepatic function 3. Medical contraindications to major abdominal surgery 1. Common hepatic artery invasion 2. Main portal vein invasion 3. Invasion of multiple extrahepatic organs 1. N2 lymphadenopathy (peripancreatic [head only], periduodenal, perioportal, celiac, superior mesenteric, or paraaortic nodes) 2. Any distant metastases (M1) including even a solitary liver metastasis, or lymph nodes in the body or tail of the pancreas

managing GBCA often lies in determining which factors apply to ultimately decide whether a patient has resectable disease.22 Table 3 illustrates the criteria to help the surgeon decide whether resection is an appropriate option in a patient with GBCA. Following patient selection, it is clear that either radical liver resection or extended liver resection in GBCA does have survival benefit in selected cases.23-25 However, surgical resection (the only potentially curative treatment) is only possible in 25% to 50% of patients at presentation.26 Then, does cholecystectomy allow for adequate survival rates in early stage tumors? Typically, GBCA spreads by either direct hepatic invasion and/or lymph node metastases. However, because preoperative computed tomography or magnetic resonance imaging is much better for identifying the depth of invasion, it is often the main variable for operative decisionmaking. One study showed only 38% detection of pathologically positive lymph nodes in patients with GBCA preoperatively.27 Therefore, evaluation of GBCA is best understood in light of the tumor invasion while emphasizing the significance of lymph node-positive disease. What are Other Options in the Preoperative Evaluation? Role of FDG-PET. Sparse data exist on the utility fluorodeoxyglucose-positron emission tomography (FDG-PET) in GBCA. It is clear that FDG-PET is not as useful with bile duct cancers as with other gastrointestinal malignancies.28 While a small series from Vanderbilt University looked at GBCA and CC and found a sensitivity of 78% in GBCA and nodular CC, the investigators noted that the study was not useful for patients with infiltrating CC.28 Conversely, PET is more useful for discovering metastatic disease. The problem is the high false-negative rate that is often caused by the low volume of metastatic disease in patients when cross-sectional imaging is negative. Likewise, there are a significant number of false-

Cholangiocarcinoma and gallbladder cancer positives because of biliary stents and inflammation from recent cholecystectomy. Currently, selective use of the PET scan should be endorsed, and it should not be used in cases of potentially resectable GBCA and bile duct cancer. Role of Staging Laparoscopy. Staging laparoscopy allows for the ability to rule out metastatic disease without subjecting a patient to an open procedure. In some cases, it can allow identification of peritoneal and liver metastases to avoid an extensive surgical exploration. Weber et al29 from Memorial Sloan-Kettering Cancer Center (New York, NY) studied 100 patients with potentially resectable HICC (n ⫽ 56) and GBCA (n ⫽ 44) that underwent staging laparoscopy before surgical exploration. Interestingly, they reported that 69% of the patients were unresectable (HICC, 59%; GBCA, 82%). Furthermore, they found that the laparoscopy yield was 48% in patients with GBCA, and the rate was higher in those without previous cholecystectomy (56%). But, in those with HICC (particularly the infiltrating type), laparoscopy was less useful (25%). Laparoscopy was found to be better at discovering peritoneal metastases than in identifying unresectable disease in locally advanced HICC. In an earlier series, staging laparoscopy correctly identified unresectable disease and thus prevented unnecessary exploration in one third of patients. The yield of laparoscopy was better for GBCA than HICC. However, the yield was improved with stratification for patients with lesions that were more suspicious for T2 or T3 disease as they have a higher incidence of metastatic disease. These patients with primary GBCA have a high incidence of metastatic disease and should undergo laparoscopic staging before attempting a resection.30 Therefore laparoscopic staging should be reserved for selected cases with focus on GBCA, particularly in those with locally advanced disease in which the surgeon thinks that the resectability is marginal. When is Radical Surgery Indicated for Gallbladder Cancer? Studying the earliest stages of the disease, incidental Tis or T1 GBCA discovered in specimens following laparoscopic cholecystectomy do not warrant further surgery if the cancer is limited to the lamina propria-muscularis layer and if a subsequent staging work-up is negative (Table 4). These patients have a 5-year survival rate ranging from 90% to 100%.31 In the past, some argued that T2 cancers with negative margins may only require a simple cholecystectomy. More recent data suggest that this is not the case. A study from Memorial Sloan-Kettering Cancer Center showed that even in T2 GBCA, extended or radical resection affords an improved survival over cholecystectomy alone.32 Unless a patient has clear contraindications to resection, surgical exploration should be attempted. Recent advances in preoperative staging, surgical technique, and perioperative management have significantly improved the morbidity and mortality rates following aggressive resections for GBCA.26 Gallbladder cancer typically invades directly into the hepatic parenchyma, the hepatic hilum, and the right portal pedicle. Thus, there are established criteria for performing an

S115 Table 4 Surgical Management of Gallbladder Cancer Management Accepted

Somewhat controversial

More controversial

Extent of Resection Liver resection of gallbladder bed Hilar lymphadenectomy CBD resection with reconstruction if positive cystic duct margin Selected use of more major resection Routine segment IV/V liver resection Routine CBD resection with reconstruction Routine trocar site excision Routine right trisectorectomy Routine radical lymphadenectomy

en bloc liver resection of the gallbladder bed and typically a hilar lymphadenectomy in the porta hepatis (hepatoduodenal ligament) and superior pancreatic nodes for patients with T2 or more invasive disease. CBD resection with reconstruction should definitely be performed if the cystic duct margin is positive. Evidence has also pointed to the selected use of more aggressive segment IV and V resections if the extent of tumor dictates.31,33 Therefore, for a T2 GBCA, an extended en bloc resection with lymphadenectomy should be performed. In contrast, for T1 cancers that are margin negative, cholecystectomy alone may be appropriate.34 However, there are clearly cases of GBCA where T3 disease is extensive. Anatomically, the gallbladder straddles the left and right hepatic lobes. In these cases where negative resection margins cannot be obtained with an anatomic resection of segments IV and V, an extended right hepatectomy should be performed.35,36 Similarly, CBD resection and hilar lymphadenectomy may be reserved for selected cases of T2 or more invasive disease because there is the potential of improved survival in patients with the metastases limited to the regional nodes. At our institution, we typically will perform such an operation. Conversely, there is no data to support radical lymphadenectomy of retropancreatic and aortocaval nodes in an effort to improve patient survival. Routine Segment IV/V Liver and CBD Resection With Biliary Reconstruction Rather than performing an en bloc resection with at least 2-cm margins, some clinicians have advocated the routine resection of segments IV and V to allow for more of an anatomic resection to reduce bleeding, parenchymal defunctionalization, and the potential for an R1 resection. In parallel, routine resection of the CBD, despite a negative cystic duct margin, has gained some popularity. There are no conclusive data from randomized trials to show that this is mandatory in patients with Tis, T1, or T2 disease where a negative margin is obtained. It is routine to perform a more extensive liver resection and a CBD resection primarily to remove the tumor and clear the lymphatics in the hilum. Despite this, data would suggest that there is not a clear difference in the number of lymph nodes (ie, three to four) with resection of the

J.K. Sicklick and M.A. Choti

S116 bile duct compared with simply selecting lymph nodes or in survival rates compared with other approaches.37 Nevertheless, it may be that clearing the lymphatics is beneficial. Again, like the use of PTC in the management of extrahepatic CC, this is an institutional philosophy and preference. Routine Right Trisectorectomy With Radical Lymphadenectomy Although groups in Japan have argued that extended right trisectorectomy with caudate lobectomy, lymph node dissection, and biliary reconstruction are necessary for radical resection of GBCA,38 this remains poorly studied. Similarly, it is unclear whether resection of lymphatics by routinely excising the extrahepatic biliary tract in all cases of GBCA needs to be performed.39 Because of the dearth of supporting data, at this time, we prefer to err on the side of more conservative therapy unless the margins of the tumor dictate further resection. Routine Trocar Site Excision Finally, as previously noted, approximately 10% of GBCA is diagnosed following laparoscopic cholecystectomy for suspected benign disease. One potential complication of this procedure in cases of subsequently diagnosed GBCA is the incidence of recurrence along trocar tracks, despite Tis disease, T1 disease, or a subsequent hepatic resection performed for attempted cure. One report found a 32% recurrence rate appearing as a new or enlarging abdominal wall mass on physical examination and/or computed tomography scanning for follow-up of disease.40 Similar concerns are recognized in the treatment of colon cancer with laparoscopic resection. Therefore, some groups advocate for the routine excision of trocar sites in patients initially undergoing simple cholecystectomy for “inapparent” GBCA.

Conclusion Clearly CC and GBCA are very different diseases. When one observes the pattern of recurrence and considers surgical therapy, there is rationale to separate these diseases. Hilar cholangiocarcinomas are often localized, slow-growing tumors. Some have described them as nonaggressive malignancies in aggressive locations. In contrast, GBCA typically has a systemically aggressive pattern. The pattern of recurrence for GBCA is often distant, whereas loco-regional recurrence is common in HICC, particularly in those where the margins are positive. But, HICC can tend to recur locally, even when the margins are negative.41 Therefore, aggressive surgical therapy is more defensible for HICC than for GBCA. In light of these arguments, some debate exists regarding the role of adjuvant therapy. But to date, there is no prospective randomized clinical trial that shows a role for adjuvant therapy for CC or GBCA. Thus, there is no evidence of benefit for the use of brachytherapy or external-beam radiation therapy in the setting of either HICC or GBCA. There are some retrospective series that suggest a limited benefit with radiation therapy.42 In the absence of compelling data supporting routine adjuvant or neoadjuvant therapy, good surgical therapy is a patient’s only chance for treating these malignancies. In summary, what are the controversies in surgical man-

agement? First, how extensive of a preoperative evaluation is required? Certainly in extrahepatic CC, evaluation of the biliary tree via magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography is essential in conjunction with cross-sectional imaging. In contrast, the role of FDG-PET scan is somewhat limited in the authors’ opinion. Preoperative biliary stenting and laparoscopy may be indicated in selected cases, although this remains controversial. How extensive a surgical resection is required? Although our approach remains unsupported by definitive data, we would recommend an aggressive surgical approach as indicated by the disease, particularly in the absence of persuasive data to support a role for adjuvant therapy.

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