With an incidence of approximately 3000 cases annually in the United States (incidence 1.14 per 1000,000 people), gallbladder cancer it accounts for only 0.5% of all gastrointestinal tract malignancies in this country.1–3 Incidence increases with age and is two to three times higher in women than in men. Worldwide, the highest incidence rates (up to 8.0 per 100,000 in men and 22 per 100,000 in women) occur among populations in the Indian subcontinent, in the Western part of South America (eg, Colombia and Ecuador), and to a lesser extent in East Asia and Eastern Europe. In the United States, the incidence is higher in American Indians and in Hispanics.2,4 The best characterized risk factor for the development of gallbladder cancer is chronic inflammation associated with gallstones (Table 65-1). Although only a small fraction of patients with cholelithiasis will develop gallbladder cancer, gallstones are present in 70% to 90% of patients diagnosed with gallbladder cancer.4–6 Further, the geographic pattern of gallbladder cancer incidence correlates with that of cholelithiasis.
Other factors implicated to increase the risk of developing gallbladder cancer include porcelain gallbladder, adenomatous polyps of the gallbladder (in contrast, cholesterol and inflammatory polyps and adenomyomatosis are not believed to be the risk factors), chronic infection with Salmonella typhi, carcinogen exposure (eg, increased risk has been reported for miners exposed to radon), obesity, and abnormal pancreaticobiliary duct junction (APBDJ). In this latter condition, a long common channel, formed by an abnormally proximal junction between the pancreatic and common bile ducts (CBDs), and elevated sphincter of Oddi pressures create a predisposition to reflux pancreatic exocrine secretions into the bile ducts. APBDJ is most prevalent in Asian countries and appears to increase the risk of development of biliary cancers, especially gallbladder cancer.7 Gallbladder cancers arising in patients with APBDJ tends to occur at a younger age, to have a lesser degree of female predominance, and to be less often associated with cholelithiasis than those arising in patients without APBDJ.
Chronic inflammation of the gallbladder mucosa related to gallstones is hypothesized to be the major factor leading to malignant transformation in most cases of gallbladder cancer. The progression from dysplasia to carcinoma in situ (CIS), then to invasive cancer has been described for gallbladder cancer, although a less common pathway involves progression of adenomas to gallbladder cancer.8 Reports outlining the molecular changes associated with this progression are emerging: frequently altered genes include p53, K-ras, P16INK4A, and ERBB2/HER2.9,10
Gallbladder cancers arising from adenomas may be associated with a distinct pathogenetic mechanism, especially when compared to those arising in patients with APBDJ. Adenomas have a high prevalence β-catenin mutations, whereas dysplastic lesions and cancers associated with APBDJ have a high prevalence of K–ras mutations and a low prevalence of β-catenin mutations. p53 and P16INK4A mutations are not seen in adenomas or dysplastic lesions, and thus appear to be later events in gallbladder carcinogenesis.10
Eighty percent of primary gallbladder cancers are adenocarcinomas. Other histological types include small cell cancer, squamous cell carcinoma, lymphoma, and sarcoma. Gallbladder cancers are also classified according to morphology as infiltrative, nodular, papillary, or a combination of these types. Papillary cancers tend to grow within the gallbladder lumen and are less likely to invade the liver or to metastasize to lymph nodes; they are associated with the best prognosis. Infiltrative or nodular cancers have a more diffuse pattern of growth that is difficult to recognize on imaging studies. These lesions are more likely to have invaded the liver and to have metastasized to lymph nodes by the time of diagnosis.
In the absence of advanced disease, patients with gallbladder cancer are asymptomatic or have symptoms such as abdominal pain, anorexia, nausea, and vomiting that may be indistinguishable from those of cholelithiasis or cholecystitis. Due to these nonspecific symptoms, a diagnosis of gallbladder cancer is not made preoperatively in over half the cases and is often an unexpected finding on pathologic review of gallbladders removed for presumed benign (gallstone) disease. With advanced disease, patients can present with weight loss, obstructive jaundice (due to tumor invasion into the biliary tree or to liver metastases), and duodenal obstruction. Signs associated with advanced disease include palpable abdominal masses, hepatomegaly, and ascites.
Laboratory tests may suggest obstructive jaundice if this condition is present; otherwise, they are not helpful in the diagnosis of gallbladder cancer. Tumor markers such as carcinoembryonic antigen (CEA) or CA 19-9 may be elevated; however, they lack sufficient sensitivity or specificity to be useful in clinical decision-making for individual patients.
Patients with suspected gallstone- or gallbladder-related conditions typically undergo transabdominal ultrasonography (US). Findings suggestive of gallbladder cancer on ultrasonography include mural thickening or calcification, a gallbladder mass greater than 1 cm in diameter, and loss of the normal gallbladder wall–liver interface (Fig. 65-1). Relative to transabdominal ultrasonography, endoscopic ultrasonography (EUS) offers greater accuracy in assessing depth of gallbladder wall penetration by masses and regional lymph node enlargement and also may provide better characterization of gallbladder masses. As EUS is invasive and does not necessarily provide more clinically relevant information than other noninvasive imaging modalities, it is not widely utilized. EUS-guided biopsy, however, is an effective technique in cases in which a tissue diagnosis is required.
Cross-sectional imaging (ie, either computed tomography [CT] scanning or magnetic resonance imaging [MRI]) should be performed on patients suspected of having gallbladder cancer. CT is typically more widely available and less expensive than MRI. Findings of gallbladder cancer include a mass protruding into the gallbladder lumen or completely replacing the gallbladder and focal or diffuse thickening of the gallbladder wall (Fig. 65-2). CT scanning also offers information on the presence or absence of distant metastases, regional lymph node involvement, and local invasion into the liver and porta hepatis.
MRI, particularly with magnetic resonance cholangiopancreatography (MRCP), can offer additional information on invasion into the liver. It is not known, however, whether routine MRI adds to the results obtained from CT scan, and thus it should be used selectively, for instance when CT findings are equivocal or precise delineation of biliary anatomy is warranted. Endoscopic or percutaneous cholangiography is not indicated for diagnostic purposes, and is reserved for therapeutic purposes. Similarly, diagnostic angiography has been replaced by CT and MRI angiography, which provide detailed imaging of vessels in the porta hepatitis.
While fluorodeoxyglucose (FDG) positron-emission tomography (PET) has not been universally accepted as a part of the routine staging evaluation for gallbladder cancer,11 retrospective studies show that gallbladder cancer tends to be FDG-avid, and that when utilized PET is more sensitive than CT for the detection of distant metastases, and therefore alters management in a significant fraction of cases when used.12–14 PET is less useful in differentiating benign versus malignant disease, and therefore is limited in its ability to differentiate between residual disease and post-surgical changes after cholecystectomy. While some favor the routine use of PET, others favor using PET selectively to further evaluate indeterminate findings on CT or MRI.
Several staging systems for gallbladder cancer have been described. The Nevin staging system and the Japanese Biliary Surgical Society system are mainly of historical interest. The American Joint Committee on Cancer (AJCC) staging system,15 now in its eighth edition (Table 65-2), which is based on the tumor depth, regional nodal involvement, and the presence of distant metastasis (tumor-node metastasis [TNM]) is currently the most widely used staging system. The current AJCC staging system numbered stages are useful in determining prognosis as well as for guiding appropriate treatment according to current paradigms.
Surgical resection is the only known curative form of therapy for gallbladder cancer. For patients in whom surgical exploration is contraindicated because of medical comorbidities or due to metastatic or unresectable disease, a percutaneous or endoscopic needle biopsy can be obtained to confirm the diagnosis. For patients in whom surgery is planned, a preoperative biopsy is contraindicated, as gallbladder cancer has a propensity for dissemination along needle tracts.
Recommendations for surgical treatment according to disease stage are given below. Specific technical issues are discussed subsequently.
Adenomas and gallbladder calcification have been associated with the risk of developing cancer or even harboring occult malignancy, and thus the management of these findings warrants specific discussion. While gallbladder polyps are noted in approximately 5% of patients undergoing gallbladder ultrasonography, not all polyps are adenomas. In fact, most are cholesterol polyps. Inflammatory polyps, hyperplastic polyps, and adenomyomatosis among other lesions can also appear as polypoid lesions in the gallbladder. Adenomyomatosis, which is an extension of Rokitansky-Aschoff sinuses through the muscular wall, can often be differentiated from adenomas by imaging, while distinction between adenomas and other polypoid lesions is more difficult. US can distinguish adenomyomatosis from other polypoid lesions in many cases, but occasionally axial imaging (CT or MRI) is needed. MRI is reported to be the most accurate imaging modality for making a diagnosis of adenomyomatosis.16 Of the polypoid lesions in the gallbladder, only adenomas harbor any malignant potential. In recent series of resected gallbladder polyps, less than 20% were found to be adenomatous, and the rate of malignancy was around 5% or less.17,18 Patients evaluated for gallbladder polyps should be assessed for symptoms attributable to the biliary system. While symptoms are rarely related to polyps, if another cause cannot be found, resection is warranted. The most consistent predictors of malignancy in polyps are older patient age and larger polyp size. Of these, size is particularly important as it is quite rare for malignancy to be identified in polyps <1 cm.18,19 Thus, size ≥1 cm is the most widely accepted indication for surgery. As the coexistence of gallstones also predicts malignancy in some studies,19 some authors advocate surgery in this setting. The finding of gallbladder polyps in patients with primary sclerosing cholangitis (PSC) warrants special consideration, as polyps in this setting are more likely to be neoplastic or even malignant. Several widely accepted consensus guideline advocate surgery for all polyps in patients with PSC,20–22 while some authors recommend mandate surgery only for patients with polyps ≥8 mm in size.23
Patients with polypoid lesions of the gallbladder who do not undergo surgery should be followed with serial US unless a diagnosis other than adenoma is confirmed. Polyps that increase in size have a high chance of being neoplastic and should be resected.24 There are little data to guide the frequency and duration of surveillance. It is reasonable to obtain an US at 6 months, 1 year, and then yearly. As polyps <5 mm are most frequently non-neoplastic, it is likely not necessary to follow these lesions beyond 1 year if they are stable in size.
The operative approach for the patient with a polypoid lesion of the gallbladder should be carefully considered. Until recently, an open approach was favored whenever the possibility of malignancy was considered. As the probability of malignancy is quite low in cholecystectomies performed for presumed gallbladder polyps, laparoscopic cholecystectomy is an appropriate treatment for early-stage (T1a) cancer (see below) and as the outcome for cancers confined to the gallbladder is not dramatically worse when laparoscopic cholecystectomy is performed as the initial treatment, it is reasonable to start with a laparoscopic approach in selected cases. The patient needs to be aware that if malignancy is found, open exploration an extended resection may be indicated (see below). This can be performed in the same setting based on frozen section results. The laparoscopic approach should be reserved for cases where the preoperative imaging does not indicate features suggestive of malignancy. Similarly, if on preoperative imaging the mass is adjacent to the liver hilus, stronger consideration should be given to initial en bloc resection of the gallbladder with the cystic plate of the liver (see below). Lastly, there should be a low threshold for conversion to an open approach (eg, for findings concerning for more advanced tumors or with concern for violation of the gallbladder with bile spillage).
Calcification of the gallbladder is an uncommon condition related to chronic cholecystitis. The term “porcelain gallbladder” typically refers to the end-stage of the process with diffuse calcification of the gallbladder wall, often detected on plain abdominal x-rays, resulting in a brittle gallbladder with a bluish discoloration. Older series reported extremely high rates of malignancy associated with gallbladder calcification, and thus cholecystectomy was advocated. Modern series, however, report a much lower incidence of gallbladder carcinoma,25 and thus routine cholecystectomy has fallen out of favor. The pattern of calcification may be important in determining the risk of malignancy, as patients with selective mucosal calcification or incomplete calcification of the gallbladder wall appear to be at higher risk than those with complete gallbladder wall calcification.26,27 Thus, it is reasonable to reserve routine cholecystectomy for symptomatic patients and those with incomplete calcification. As cholecystectomy is a low-risk procedure and even minimal risk of harboring an aggressive malignancy may be unacceptable, surgery can also be considered in low surgical risk patients with asymptomatic complete gallbladder calcification.
For Tis (carcinoma in situ) and T1a (cancer that invades the lamina propria but does not extend into the muscularis) lesions, the available retrospective data suggest that simple cholecystectomy is sufficient therapy in most cases, with a cure rate approaching 100%. These lesions are most frequently detected on pathological examination of gallbladders removed for presumed benign disease. Patients diagnosed with gallbladder cancer in this manner should undergo formal imaging-based staging, and the cholecystectomy specimen should be carefully examined to ensure that all margins are negative for cancer. Patients with imaging studies that reveal no evidence of residual or metastatic gallbladder cancer and are found to have a cystic duct margin that is positive for cancer should undergo reexploration with resection to a negative margin, which may involve common duct excision and hepaticojejunostomy. In contrast, patients with negative margins and negative imaging studies who undergo no additional treatment for their gallbladder cancer have excellent outcomes that are unlikely to be improved by radical surgery.28
The management of T1b (cancer that invades the muscularis but does not extend into the perimuscular connective tissues) lesions has been controversial. In published series, the 5-year survival rate for patients with T1b gallbladder cancer having undergone radical resection averages 87.5%, whereas it averages only 61.3% in patients having undergone simple cholecystectomy alone.29 Further, a recently published decision analysis suggests that radical surgery (described later for stage II cancers) is associated with improved survival compared to that associated with simple cholecystectomy alone in most patients with T1b gallbladder cancer.29 Therefore, we treat patients with T1b gallbladder cancer in the same way we treat patients with T2 gallbladder cancer.
Patients found to have a T2 (cancer invasion into the perimuscular connective tissues of the gallbladder) lesion in their cholecystectomy specimen following surgery for presumed benign disease should undergo staging (as described earlier), and in the absence of contraindications, radical resection. Simple cholecystectomy is performed using a subserosal dissection plane, as the serosa of the gallbladder is continuous with Glisson’s capsule of the liver and thus there is no serosa between the gallbladder and the gallbladder fossa of the liver. Hence simple cholecystectomy may leave positive margins in the gallbladder fossa. Indeed, reexploration reveals residual tumor in 40% to76 % of these cases.30–33 In addition, the probability of regional lymph node metastasis in patients with T2 gallbladder cancer has been reported to range from 28% to 63%.30–33 These findings provide rationale for performing reexploration with liver resection and portal lymphadenectomy. There is convincing, albeit retrospective, evidence that such radical surgery is associated with improved survival for patients with T2 gallbladder cancer.30–37
A role for aggressive surgical resection for some stage III gallbladder cancers has been receiving increasing recognition. This stage includes T3 lesions (locally advanced cancers that perforate the gallbladder serosa or directly invade the liver and/or one adjacent organ) and T1 to T3 lesions associated with regional lymph node metastasis. Some have advocated neoadjuvant chemotherapy or neoadjuvant chemoradiation for this group of patients in order evaluate the biology of disease and better select patient for surgery.
Surgery for patients with T3 lesions requires careful planning and must be tailored to individual patients. For some patients with liver invasion, hepatic resections encompassing segments 4b and 5 may be sufficient. However, because the gallbladder fossa bridges both right and left hemilivers, and due to the proximity of the cystic plate to the inflow of the right liver, extended right hepatectomy is often required. Adjacent involved structures, such as the hepatic flexure of the colon, should be resected en bloc. Long-term survival rates ranging from 15% to 63% have been reported from some centers to be associated with these extended procedures for T3 lesions.30–37
While the outcome for patients with lymph node metastases in the porta hepatis (N1) is considerably worse than for patients without uninvolved nodes (N0), the surgical approach is generally the same. The only possible exception would be the exceedingly unusual circumstance where a patient with a T1a tumor is diagnosed with N1 disease in the absence of distant metastases. In such a scenario regional lymphadenectomy would be required.
Stage IVA (invasion of the main portal vein, hepatic artery, multiple extrahepatic organs) and stage IVB (N2 and/or distant metastasis) disease is generally considered unresectable. Reports of radical procedures involving resection of the main portal vein and/or common hepatic artery exist, but these procedures are associated with increased morbidity and mortality rates without any proven survival benefit. The outcome of patients with multiple regional lymph nodal metastases (N2 disease) is similar to patients with M1 disease, and these patients are not thought to benefit from resection.
There is no evidence that debulking cholecystectomy provides any therapeutic or palliative benefit.
The surgical approach depends both on the stage of disease (as outlined above) as well as the clinical presentation. There are three common scenarios in which gallbladder cancer is discovered: (1) it can be found on pathologic review of a cholecystectomy performed for presumed benign disease; (2) it can be suspected or diagnosed preoperatively, either resulting from a workup for symptoms attributable to the tumor or found incidentally; or (3) it can be discovered intraoperatively, often on exploration for presumed cholecystitis. Specific considerations for each clinical scenario will be discussed separately.
When gallbladder cancer is diagnosed after a previous cholecystectomy, the pathology report, the operative report, and any imaging obtained prior to the cholecystectomy should be thoroughly reviewed. In addition to depth of penetration and margin status, particularly that of the cystic duct, the pathology report can provide information on tumor location. Similarly, pre-cholecystectomy imaging can provide information on tumor location as well as possible liver or nodal involvement. Knowing the tumor location (ie, neck, body, or fundus; abutting liver, or on the side of gallbladder away from liver) may help in operative planning and in the interpretation of the operative findings on reexploration. After completing the staging evaluation as above, patients with T1b-T3 tumors are prepared for reoperation. Given the propensity of gallbladder cancer to seed wound sites, reexcision of all surgical wounds, including laparoscopic port sites, has been recommended. However, port site metastasis is usually associated with other peritoneal metastases and excision of port sites has not been proven beneficial.38
The operative report from the prior cholecystectomy and/or discussion with the surgeon can elicit findings suggestive of disseminated disease within the abdomen. In the absence of such findings, a diagnostic laparoscopy is unlikely to be beneficial in this setting.
We generally use an extended right subcostal incision that starts in the upper midline below the xiphoid and curves to a form a line subcostally on the right side that can extend as far as a point midway between the inferior costal margin and anterior superior iliac spine if necessary. We first conduct a thorough examination for metastases. Often, hilar and celiac lymph nodes can be palpated before opening the entirety of the incision. The liver and peritoneal surfaces are also inspected.
The scope of the operation then performed is similar to that described by Glenn and Hays in the 1950s, which entailed resection of the gallbladder fossa of the liver as well as a regional lymphadenectomy of the hepatoduodenal ligament (Fig. 65-3).39 We typically will perform the lymphadenectomy first. The hilar lymph node dissection proceeds similarly to that described below for perihilar cholangiocarcinoma, with the notable exception being that the bile duct is not routinely resected and is instead skeletonized along with the portal vein and hepatic artery. Some authors have advocated division of the bile duct, particularly as this facilitates the nodal dissection. While it is true that this makes the lymphadenectomy easier, it is associated with greater morbidity without improving nodal yield or survival.35,37,40,41 As with perihilar carcinoma, on performing the Kocher maneuver and initiating the hilar dissection, retropancreatic, celiac, periaortic, and pericaval lymph nodes can be inspected and palpated. Hard or enlarged nodes are sampled and subjected to frozen-section analysis. If these lymph nodes are positive for metastases, M1 disease is present and radical resection is aborted.
In the reoperative setting it is not uncommon for fibrosis to be encountered in the porta hepatis. It may be difficult to differentiate fibrosis from tumor. Information gleaned from review of the pathology report and the pre-cholecystectomy imaging (eg, tumor location and cystic duct margin status) may aid in this assessment. If invasion of the common duct is suspected, the extrahepatic biliary system can be resected from the superior border of the duodenum to just below the bifurcation. Common duct resection may also facilitate resection of bulky nodal disease in the hepatoduodenal ligament. The CBD is clamped and transected at the superior border of the duodenum. Similarly, the common hepatic duct is transected near its bifurcation. We take care to minimize spillage of bile that may contain cancer cells. The distal bile duct is oversewn with a slowly absorbable monofilament suture such as polydioxanone (PDS). The proximal bile duct is reconstructed with a Roux-en-Y hepaticojejunostomy as described below. If invasion of the right inflow (right portal vein or right hepatic artery) is found, an extended right hepatectomy is performed. We consider invasion of the main portal vein or proper/common hepatic artery to be unresectable and do not perform major vascular resection and reconstruction for advanced gallbladder cancer at our institution.
We then proceed to the liver resection. The gallbladder fossa of liver needs to be resected with at least a 2-cm margin. Although a nonanatomic liver resection can be performed, we favor a segmental resection of liver segments 4b and 5, which may be associated with less intraoperative bleeding.42 The basic conduct of a liver resection is discussed elsewhere; however, some points bear mentioning. Intraoperative US is usually performed and may help in providing information on the intrahepatic vascular anatomy as well as occult metastatic disease. The segmental portal pedicles are usually controlled within the liver parenchyma. As the middle hepatic vein is located directly anterior to the gallbladder fossa, separating segments 4b and 5, care must be taken to avoid bleeding from the vein and its branches. The base of the gallbladder fossa is in close proximity to the porta hepatis, and precaution should be given at the end of the liver resection when these structures are approached. In particular, injury to the right anterior portal pedicle and the portal pedicle of segment 8 within the liver should be avoided. The routine use of more extended liver resections has not been proven to be of benefit.40
For patients suspected of having resectable gallbladder cancer, the approach is similar. In this setting, we begin surgical exploration with laparoscopy, as even with a complete radiologic staging workup disseminated disease is occasionally found, and in these cases laparotomy can be spared.43 The degree of suspicion for gallbladder cancer beyond T1a must be determined preoperatively. The approach for polypoid lesions, which generally do not harbor malignancy, is described above. For masses with features concerning for malignancy, we do not perform laparoscopic cholecystectomy because of the risk for gallbladder perforation and tumor spillage. In these cases extended cholecystectomy is usually performed as the initial procedure. In some cases, frozen-section analysis may be used either prior to performing the extended cholecystectomy or after an extended cholecystectomy but prior to the lymphadenectomy. Although determining depth of cancer invasion can be difficult on frozen sections, these grossly apparent cancers are likely to be at least T1b. For masses with invasion beyond the gallbladder, intraoperative diagnosis is not needed. It should be noted, however, that rarely benign conditions, in particular xanthogranulomatous cholecystitis, can mimic this condition. In the case of suspected resectable gallbladder cancer with invasion beyond the gallbladder (T3 tumors), extended liver resections and/or en bloc resection of adjacent organs may be required. Gallbladder cancers presenting with obstructive jaundice due to involvement of the bile duct are typically very advanced tumors. A resection with curative intent can rarely be performed and even when performed, long-term survival is rare.44
In cases where gallbladder cancer is diagnosed intraoperatively but was not suspected preoperatively, a thorough inspection of the liver and peritoneum for metastatic disease should be performed. If cancer is discovered during an open procedure, the porta hepatis and celiac origin should be palpated for nodal involvement. If extensive dissection has not begun, it is appropriate to close the patient and complete the radiologic staging exam. Similarly, if the gallbladder has been completely resected and frozen section reveals cancer, it likely wise to terminate the operation so as to complete staging and consent the patient prior to performing radical resection. In some cases, gallbladder cancer may be discovered late in the procedure when difficulty is encountered in attempting to remove the gallbladder from the gallbladder fossa of the liver. In this circumstance, if expertise is available, it may be appropriate to perform an extended cholecystectomy and proceed to lymphadenectomy if frozen section confirms gallbladder cancer.
Adjuvant chemoradiotherapy is commonly administered after resection of gallbladder cancers. External beam or intraoperative radiation therapy alone or in combination with 5-flourouracil (5-FU) has been associated with diminished rates of local recurrence. Recently results, of the phase III multicenter BILCAP trial from the United Kingdom, were reported in abstract form. This trial randomized 447 patients with gallbladder (18%) and biliary cancer (19% intrahepatic, 28% perihilar, 35% distal) to capecitabine or observation following complete surgical resection. Although in the intention to treat analysis, the benefit in median overall survival for capecitabine did not reach significance (51 months versus 36 months, p = 0.097), the result was significant in the per protocol analysis (53 months versus 36 months, p = 0.028).45 Subgroup analysis from an older phase III trial randomizing 508 patients with pancreaticobiliary cancer (28% gallbladder cancer and 27% cholangiocarcinoma) to adjuvant treatment with fluorouracil and mitomycin C or observation showed improved survival with adjuvant treatment for patients with gallbladder cancer but not cholangiocarcinoma.46
Of the several approaches that have been applied in patients with advanced gallbladder cancer, the only regimen supported by level one evidence is the combination of gemcitabine plus cisplatin. Data from a multicenter randomized controlled trial (Advanced Biliary Cancer (ABC)-02 trial) published in 2010 of patients with locally advanced or metastatic biliary tract cancer (of whom ∼36% had gallbladder cancer) demonstrated that the combination of gemcitabine plus cisplatin is associated with improved overall and progression-free survival compared to gemcitabine alone.47 As such, this gemcitabine-cisplatin combination represents the current standard treatment option for patients with advanced biliary tract cancers, including gallbladder cancer.11 It should also be noted that based on the impressive results found for colorectal cancer with defective mismatch repair, patients with other solid tumors harboring defective mismatch repair were examined for response to the anti–PD-1 antibody pembrolizumab. In a series of 86 patients, including 4 with cholangiocarcinoma, responses were seen regardless of the cancers’ tissue of origin.48 Pembrolizumab is now approved for the treatment of patients with all metastastic and unresectable solid tumors having defective mismatch repair who have progressed through prior therapy and for whom there are no satisfactory treatment alternatives. Palliation of biliary obstruction, which can be required for advanced gallbladder cancer (Figs. 65-4 and 65-5), is discussed below.
Data derived from the National Cancer Database support the nihilistic view traditionally associated with gallbladder cancer.49 In these population-based data, 5-year survival rates for patients with T1N0, T2N0, and T3N0 (or node-positive) disease are 39%, 15%, and 5%, respectively.
However, contemporary surgical series suggest that substantially improved outcomes can be achieved by the application of surgical resection of gallbladder cancers.31–37 In these reports, 5-year survival rates following resection of T1 lesions range from 85% to 100%. With radical resection of T2, T3, and T4 lesions, reported 5-year postoperative survival rates range from 41% to 90%, 15% to 63%, and 2% to 25%, respectively. Radical resection of node-positive disease has been reported to be associated with 5-year survival in as high as 60% of patients, although some reported series contained no patients who survived 2 or more years among those with lymph node metastasis.30–37
Reported morbidity and mortality rates associated with resection of gallbladder cancers range from 5% to 54% and from 0% to 21%, respectively. In general, the highest morbidity and mortality rates are associated with series describing more extensive resections.
The best reported outcomes among patients with unresectable biliary tract cancers are those from the ABC-02 trial. The median overall survival among patients treated with the combination of gemcitabine and cisplatin was 11.7 months, whereas it was 8.1 months in those treated with gemcitabine alone.47
