Surgical Resection for CCA: Current Curative Strategy for a Once Uniformly Fatal Disease
Yuman Fong, MD
Murray F. Brennan Chair in Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
The proximity of cholangiocarcinoma (CCA) to the major nutrient vasculature for the liver makes them often life threatening at the time of diagnosis, extraordinarily difficult to treat and almost uniformly fatal with liver failure or biliary sepsis within months of presentation. However, over the last decade, great strides have been made in diagnosis and surgical treatment of CCA.
Peripheral CCA
These malignancies arise from ducts beyond the main right or left hepatic ducts, may grow to significant size before diagnosis and may be incidentally found during workup for abnormal liver function tests or abdominal pain. The apparent rise in incidence is the result of better diagnosis. Because these tumors tend to spread by intraductal or portal venous dissemination, many tumors are associated with satellite lesions (or small nodules within proximity of a large dominant tumor) or show multiple tumors. Thus, many were once thought to be metastatic tumors of unknown origin, and patients were treated only with chemotherapy. With enhanced diagnostic studies, including multi-organ endoscopies, whole-body metabolic scans such as positron emission tomography (PET) to rule out primary cancers, and immunohistochemistry of biopsies (AE1, CK7, CK20, CDX2), a diagnosis of primary CCA can be reached.
The most significant recent advance is the recognition of these tumors as primary liver cancers and treatment with liver-directed therapies, with many more cases undergoing surgical resection than before. With surgical resection, a cure rate of 30 percent to 60 percent can be achieved in these patients.1-6 Operative mortality from these extensive operations is uniformly less than 5 percent due to improvements in imaging for surgical planning and surgical technique. Patients often require regional lymphadenectomy because of the high (9 percent to 50 percent) chance of having lymphatic metastases (table 1).1-4 In patients with node-negative cancer, many series report a >50 percent cure rate.
Because patients generally die of liver recurrence, other regional therapies were tested as treatments of these vascular tumors:
1. Regional chemotherapy with floxuridine produced a 47 percent response rate, a median survival of 30 months and two-year survival of 67 percent.7
2. Standard particle embolization or radioembolization employing yttrium-90 particles produces tumor shrinkage.8
For systemically disseminated disease, chemotherapy using gemcitabine and oxaliplatin has proven modestly effective.9
Hilar CCA (Klatskin tumor)
These are small nodular tumors arising from either the left or right hepatic duct that grow to involve the confluence of the main bile ducts, causing jaundice or abnormal liver function tests. This was a uniformly fatal disease three decades ago. Over the few last years, outcome has improved as a result of technical improvements in surgical resection guided by superior imaging and improvements in peri-operative care.
Imaging for CCA:
1. Thin cut helical cross-sectional CT now allows detection of discontiguous liver metastases and peritoneal metastases.
2. 18F-2-fluoro-2-deoxy-D-glucose-PET scanning identifies the primary and is highly sensitive (80 percent to 100 percent) for detection of distant metastases, including peritoneal and bone metastases.10
3. Duplex ultrasound, CT angiography or magnetic resonance cholangiopancreatography define the extent of biliary infiltration, vascular involvement and vascular anomalies, and facilitate staging and planning of surgery, especially if obtained before there has been decompression of the biliary tree.
The choice of imaging test depends on local availability and expertise. My personal preference is to obtain a duplex ultrasound to assess for primary tumor extension along the biliary tree, vascular involvement and discontiguous liver metastases. In addition, I obtain a CT/PET scan with angiography phases to assess vascular anomalies and distant metastases.
Preoperative pathologic diagnosis: the definitive pathological diagnosis of CCA before or at surgery remains difficult on brush biopsy or even on intraoperative needle biopsy because these tumors have a fair amount of stroma. In fact, the sensitivity of CT scan or MRI (0.9–1) is much higher than brush biopsy (0.2–0.8), biliary cytology (0.4–0.6) or ERCP/fine needle aspiration biopsy (0.45).11 Since an unexcised tumor means certain death and the likelihood that a case with the radiologic and clinical picture of CCA turns out to be benign (e.g. sclerosing cholangitis) in <5 percent of the time, most experienced surgeons would perform a definitive cancer operation based solely on a clinical and radiologic diagnosis.
Preoperative drainage of the biliary tree prior to attempted resection is controversial.12 The indisputable facts are: 1) drainage is associated with colonization of the biliary tree and higher likelihood of post-operative infection, 2) any vascular compromise during or after surgery in the jaundiced liver can produce hepatic necrosis and 3) any hypotension in the patient with jaundice runs a high risk of renal insufficiency.
Patients who should have preoperative drainage include those with 1) renal insufficiency, 2) sepsis, 3) medical issues that require attention and 4) cases where reconstruction of the nutrient vasculature to the future liver remnant is anticipated. Great attention should be paid to avoid contaminating the undrained biliary tree. If there are signs of infection or sepsis after drainage, all three main sectors should be drained to allow resolution of biliary sepsis. In cases when drainage is indicated, I would also wait to allow resolution of jaundice prior to resection.
Portal vein embolization significantly improves safety in preoperative preparation to allow for growth of the future remnant liver prior to resection. Kawasaki first proposed this for patients undergoing resections for hilar CCA or gallbladder cancer13 since a very large section of functional liver is usually resected for a very small tumor. The portal vein on the side of the liver to be resected is occluded by particles or coils. The contralateral liver then usually grows over a period of weeks to provide for improved outcome.14 The combination of judicious biliary drainage, portal vein embolization and appropriate antibiotics have reduced the operative mortality of these resections to less than 4 percent (table 2).15-18
Resection of the liver: the most important strategy that has improved the long-term outcome of patients with hilar CCA is the inclusion of a liver resection with the resection. This is important because tumors at the confluence of the hepatic ducts almost always involve the liver parenchyma at the junction of segments four and five. When surgeons were unwilling to resect at least part of the liver, resections were likely to be associated with positive margins, which have been shown to be associated with recurrence and death.19 Figure 1 shows data from the largest series in the literature: liver resection is associated with a higher margin-negative rate and a higher survival. With the current approach of combining a major resection with resection of the bile duct tumor, greater than 25 percent of patients resected of this cancer are now cured in a disease that only three decades ago was uniformly fatal (table 2).15-22 |
References
1. DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007 May;245(5):755-62.
2. Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 2008 May;23(5):766-70.
3. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008 Jul;248(1):84-96.
4. Saiura A, Yamamoto J, Kokudo N, Koga R, Seki M, Hiki N, et al. Intrahepatic cholangiocarcinoma: analysis of 44 consecutive resected cases including 5 cases with repeat resections. Am J Surg 2009 May 8.
5. Lang H, Sotiropoulos GC, Sgourakis G, Schmitz KJ, Paul A, Hilgard P, et al. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg 2009 Feb;208(2):218-28.
6. Guglielmi A, Ruzzenente A, Campagnaro T, Pachera S, Valdegamberi A, Nicoli P, et al. Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection. World J Surg 2009 Jun;33(6):1247-54.
7. Jarnagin WR, Schwartz LH, Gultekin DH, Gonen M, Haviland D, Shia J, et al. Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol 2009 Jun 2.
8. Gulec S. Special Issue On Yttrium90 Therapies. Journal of Interventional Oncology 2[1], 1-90. 2009. 2009. Ref Type: Journal (Full).
9. Jang JS, Lim HY, Hwang IG, Song HS, Yoo N, Yoon S, et al. Gemcitabine and oxaliplatin in patients with unresectable biliary cancer including gall bladder cancer: a Korean Cancer Study Group phase II trial. Cancer Chemother Pharmacol 2009 Aug 4.
10. Corvera CU, Blumgart LH, Akhurst T, DeMatteo RP, D'Angelica M, Fong Y, et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg 2008 Jan;206(1):57-65.
11. Davidson BR, Gurusamy K. Is preoperative histological diagnosis necessary for cholangiocarcinoma? HPB (Oxford) 2008;10(2):94-7.
12. Nimura Y. Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford) 2008;10(2):130-3.
13. Kawasaki S, Makuuchi M, Kakazu T, Miyagawa S, Takayama T, Kosuge T, et al. Resection for multiple metastatic liver tumors after portal embolization. Surgery 1994 Jun;115(6):674-7.
14. Covey AM, Brown KT, Jarnagin WR, Brody LA, Schwartz L, Tuorto S, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg 2008 Mar;247(3):451-5.
15. Kawarada Y, Das BC, Naganuma T, Tabata M, Taoka H. Surgical treatment of hilar bile duct carcinoma: experience with 25 consecutive hepatectomies. J Gastrointest Surg 2002 Jul;6(4):617-24.
16. Jang JY, Kim SW, Park DJ, Ahn YJ, Yoon YS, Choi MG, et al. Actual long-term outcome of extrahepatic bile duct cancer after surgical resection. Ann Surg 2005 Jan;241(1):77-84.
17. Allen PJ, Reiner AS, Gonen M, Klimstra DK, Blumgart LH, Brennan MF, et al. Extrahepatic cholangiocarcinoma: a comparison of patients with resected proximal and distal lesions. HPB (Oxford) 2008;10(5):341-6.
18. Shi Z, Yang MZ, He QL, Ou RW, Chen YT. Addition of hepatectomy decreases liver recurrence and leads to long survival in hilar cholangiocarcinoma. World J Gastroenterol 2009 Apr 21;15(15):1892-6.
19. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001 Oct;234(4):507-17.
20. Rea DJ, Munoz-Juarez M, Farnell MB, Donohue JH, Que FG, Crownhart B, et al. Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients. Arch Surg 2004 May;139(5):514-23.
21. Nishio H, Nagino M, Nimura Y. Surgical management of hilar cholangiocarcinoma: the Nagoya experience. HPB (Oxford) 2005;7(4):259-62.
22. Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ. Surgical management of hilar cholangiocarcinoma. Ann Surg 2005 May;241(5):693-9.