Surgery remains the only potentially curative modality for cholangiocarcinoma (CCA) in any site of origin. Unfortunately, only a minority of patients are surgical candidates. In addition, despite resection, recurrence rates are high, suggesting the need for additional therapy as part of a perioperative strategy.
Most patients with CCA are elderly and sometimes have significant comorbidities. Any cardiopulmonary condition must be thoroughly evaluated before performing an invasive liver, bile duct, or pancreas resection. In addition, patients with jaundice can present with malnutrition or cholangitis that needs urgent attention with decompression and antibiotics. Complete workup for consideration of surgery then proceeds to staging of the chest, abdomen, and pelvis with cross-sectional computed tomography or magnetic resonance imaging (MRI). Indirect and/or direct cholangiography via MRI or endoscopy should be obtained with major bile duct involvement; endoscopy is warranted if biliary stenting is needed. Besides absence of metastases, the planned operation should leave an adequate future liver remnant with intact inflow, outflow, and biliary drainage. Depending on the tumor, complete resection may be comprised of a hepatectomy alone if intrahepatic, hemihepatectomy with bile duct resection if the hilum is involved, or pancreaticoduodenectomy for a distal common bile duct lesion.
Surgical management of intrahepatic CCA (iCCA) typically consists of parenchyma-sparing, nonanatomic liver resection when tumors are peripherally located. An anatomic liver resection may be required for deeper, centrally located disease or when satellites are present. Either a right or left hemihepatectomy is needed when major biliary pedicles or hepatic veins are involved by the tumor. Both of these can be extended to adjacent segments; however, one must ensure the future liver remnant is of adequate size to avoid postoperative hepatic insufficiency.
Klatskin tumors will require either left or right hepatectomy as described above in addition to cholecystectomy, extrahepatic bile duct resection, and selective caudate lobectomy. The hilar plate is lowered to exclude main portal vein invasion and determine resectability. Extrahepatic bile duct resection is performed next to determine extent of disease and to facilitate portal lymphadenectomy. The bile duct is divided distally near the head of the pancreas, and the margin is sent for frozen section analysis. The hepatic artery and portal inflow are divided extrahepatically whenever possible as is the hepatic vein outflow. The parenchyma of the liver is divided along the area of vascular demarcation or margin as determined by ultrasound. The affected right or left bile duct is typically taken intrahepatically to avoid the serious consequences of missing anatomic variations. Pathologically, the caudate lobe is involved in 40% of hilar CCA cases.
Distal CCAs are resected via pancreatoduodenectomy, or Whipple procedure, similar to pancreatic cancers in the head of the gland. This procedure consists of division of the duodenum or stomach, dissection and division of the common hepatic duct proximal to the tumor (to obtain a negative margin), cholecystectomy, and division of the neck of the pancreas and proximal jejunum. A portal and retroperitoneal lymph node dissection ensues. Subsequently, reconstruction consists of Roux-en-Y pancreaticojejunostomy, hepaticojejunostomy, and duodeno- or gastrojejunostomy. Given the absence of pancreatic duct involvement manifested by a soft gland, pancreatic leak rates are higher in Whipple procedures for distal CCA than in those for pancreatic cancer.
National Comprehensive Cancer Network guidelines for management of biliary malignancies recommends upfront surgery for those with resectable iCCA.1 However, interest has been renewed in applying preoperative chemotherapy for borderline resectable or oncologically high-risk tumors. A recent study from France examined the outcomes of iCCA resection after neoadjuvant therapy for locally advanced disease downstaged to resectability after therapy (n = 74). After a median of 6 cycles of combination gemcitabine and platinum-based chemotherapy, the authors reported a similar median overall survival (OS) in patients who received neoadjuvant therapy compared with those who underwent surgery alone: 24.1 months versus 25.7 months, respectively (P = .391).2 Both groups had improved survival compared with patients who had chemotherapy alone.
In another study of neoadjuvant therapy, of 169 patients with iCCA, 32 patients who were found initially unresectable were downstaged with preoperative chemotherapy and radiation. No difference was seen in median OS between those who underwent upfront hepatectomy and those who were treated prior to resection (32.3 months; 95% confidence interval [CI], 23.9-40.7 vs 45.9 months; 95% CI, 32.3-59.4; P = .54).3
These reports suggest that patients whose tumor biology responds to neoadjuvant therapy may be considered for surgical resection as their outcomes appear similar to those who undergo upfront resection. However, significant selection bias exists in these retrospective reports. A single-arm, prospective trial (NCT03579771) to determine feasibility of this approach using gemcitabine/cisplatin/nab-paclitaxel as neoadjuvant therapy has recently completed accrual, and the preliminary results were presented at the 2022 ASCO GI Cancer Symposium.4 All 30 patients completed preoperative chemotherapy, and 22 (73%; P = .0106) underwent curative resection. The disease control rate was 90%, and 23% of patients experienced a partial response. Pathologic response and molecular profiling information will be reported at a later date. Recurrence-free and OS data are not yet mature.
In a systematic review of outcomes of 87 patients who received neoadjuvant chemoradiotherapy prior to hepatectomy for hilar CCA,5 only 2 studies employed use of neoadjuvant therapy in patients deemed resectable at presentation (n = 37). In addition, 2 studies describing neoadjuvant therapy for initially unresectable or locally advanced hilar CCA reported 5 patients in their combined cohort (n = 17) with histologic complete response ats resection. Among pooled data, median OS was 19 months, and 5-year survival was 20%. Additional large, multi-institutional trials are necessary to determine the benefits of therapy in this setting. Of note, neoadjuvant chemoradiotherapy is a required component of liver transplant protocols for hilar CCA.
Compared with patients who underwent upfront pancreaticoduodenectomy, the 5-year OS rate of patients who received neoadjuvant gemcitabine or 5-fluorouracil was not statistically significant (46.6% in patients who received neoadjuvant therapy vs 49.1% in those who did not; P >.05).6 Several small retrospective studies have demonstrated the utility of neoadjuvant chemoradiotherapy to convert unresectable distal CCA to resectable disease. Although the largest study represented only 25 patients, R0 resection was achieved in 89.6% of all resections.7 These findings suggest the utility of neoadjuvant chemoradiotherapy in this setting, but consensus on the most effective chemotherapeutic agent or radiation modality for distal CCA is lacking.
In summary, resection for localized CCA in fit patients remains the standard of care. However, it remains to be determined if preoperative therapy will allow for better selection of patients and improve outcomes in this aggressive disease. It is possible that certain tumor sites and/or molecular subsets may benefit preferentially from this strategy.
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