Gallengangskarzinome

Gallengangskarzinome sind die zweithäufigsten malignen primären Lebertumoren nach dem hepatozellulären Karzinom. Patienten mit Gallengangskarzinomen haben eine sehr schlechte Prognose: eine 5-Jahres-Überlebensrate von unter 20% und ein medianes Gesamtüberleben von 12 – 15 Monaten [1], [2]. Dieser Beitrag fasst die Epidemiologie und die evidenzbasierten therapeutischen Optionen von Patienten mit Gallengangskarzinomen zusammen.

Kernaussagen

• 3% aller gastrointestinalen Tumoren sind Gallengangskarzinome. 70% der Gallengangskarzinome treten sporadisch auf.

• Darüber hinaus sind die wichtigsten Risikofaktoren in der westlichen Hemisphäre die primär sklerosierende Cholangitis und in Asien die parasitäre Infektion mit Leberegeln.

• Risikopatienten sollten durch eine Kombination aus Bildgebung (Sonografie, MRCP, CT), Endoskopie und Biomarkern regelmäßig überwacht werden.

• Patienten mit Gallengangskarzinomen haben eine fatale Prognose. Die einzige Therapie mit Chance auf Kuration ist die Resektion. Die Rezidivraten nach Resektion sind jedoch hoch.

• Phase-III-Studien zeigten, dass eine adjuvante Chemotherapie das rezidivfreie Überleben und das Gesamtüberleben verlängert.

• In der palliativen Situation ist eine Chemotherapie mit Gemcitabin und Cisplatin der Standard der Erstlinientherapie.

• Prospektiv randomisierte Phase-III-Daten zu systemischen Zweitlinienoptionen liegen derzeit nicht vor. Auf der Basis von Phase-II- und retrospektiven Daten sowie einer Metaanalyse kann eine 5-FU-basierte Chemotherapie angeboten werden.

• Zielgerichtete und Immuntherapien stehen aktuell im Fokus der Forschung.

Schlüsselwörter

primär sklerosierende Cholangitis - adjuvante Chemotherapie - palliative Erstlinientherapie - palliative Zweitlinientherapie - Immuntherapie

• Literatur

• 1 Valle J, Wasan H, Palmer DH. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273-1281
• 2 Okusaka T, Nakachi K, Fukutomi A. et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 2010; 103: 469-474
• 3 Blechacz B, Komuta M, Roskams T. et al. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2011; 8: 512-522
• 4 Bergquist A, von Seth E. Epidemiology of cholangiocarcinoma. Best Pract Res Clin Gastroenterol 2015; 29: 221-232
• 5 Saha SK, Zhu AX, Fuchs CS. et al. Forty-year trends in cholangiocarcinoma incidence in the U.S.: Intrahepatic disease on the rise. Oncologist 2016; 21: 594-599
• 6 Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology 2011; 54: 173-184
• 7 Erichsen R, Jepsen P, Vilstrup H. et al. Incidence and prognosis of cholangiocarcinoma in Danish patients with and without inflammatory bowel disease: a national cohort study, 1978–2003. Eur J Epidemiol 2009; 24: 513-520
• 8 Boberg KM, Bergquist A, Mitchell S. et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol 2002; 37: 1205-1211
• 9 Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002; 89: 962-970
• 10 Sriamporn S, Pisani P, Pipitgool V. et al. Prevalence of Opisthorchis viverrini infection and incidence of cholangiocarcinoma in Khon Kaen, Northeast Thailand. Trop Med Int Health 2004; 9: 588-594
• 11 Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastroenterol 2008; 24: 349-356
• 12 Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004; 24: 115-125
• 13 Gatselis NK, Tepetes K, Loukopoulos A. et al. Hepatitis B virus and intrahepatic cholangiocarcinoma. Cancer Invest 2007; 25: 55-58
• 14 Matsumoto K, Onoyama T, Kawata S. et al. Hepatitis B and C virus infection is a risk factor for the development of cholangiocarcinoma. Intern Med 2014; 53: 651-654
• 15 Lepage C, Cottet V, Chauvenet M. et al. Trends in the incidence and management of biliary tract cancer: a French population-based study. J Hepatol 2011; 54: 306-310
• 16 Shaib YH, El-Serag HB, Davila JA. et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005; 128: 620-626
• 17 Shaib YH, El-Serag HB, Nooka AK. et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study. Am J Gastroenterol 2007; 102: 1016-1021
• 18 Ringe KI, Wacker F. Radiological diagnosis in cholangiocarcinoma: Application of computed tomography, magnetic resonance imaging, and positron emission tomography. Best Pract Res Clin Gastroenterol 2015; 29: 253-265
• 19 Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145: 1215-1229
• 20 Nathan H, Aloia TA, Vauthey JN. et al. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2009; 16: 14-22
• 21 Hennedige TP, Neo WT, Venkatesh SK. Imaging of malignancies of the biliary tract – an update. Cancer Imaging 2014; 14: 14
• 22 DʼOnofrio M, Vecchiato F, Cantisani V. et al. Intrahepatic peripheral cholangiocarcinoma (IPCC): comparison between perfusion ultrasound and CT imaging. Radiol Med 2008; 113: 76-86
• 23 Guo LH, Xu HX. Contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Controversy over the ASSLD Guideline. Biomed Res Int 2015; 2015: 349172
• 24 Hann LE, Greatrex KV, Bach AM. et al. Cholangiocarcinoma at the hepatic hilus: sonographic findings. AJR Am J Roentgenol 1997; 168: 985-989
• 25 Neumaier CE, Bertolotto M, Perrone R. et al. Staging of hilar cholangiocarcinoma with ultrasound. J Clin Ultrasound 1995; 23: 173-178
• 26 Khalili K, Metser U, Wilson SR. Hilar biliary obstruction: preliminary results with Levovist-enhanced sonography. AJR Am J Roentgenol 2003; 180: 687-693
• 27 Madhusudhan KS, Gamanagatti S, Gupta AK. Imaging and interventions in hilar cholangiocarcinoma: a review. World J Radiol 2015; 7: 28-44
• 28 Fowler KJ, Brown JJ, Narra VR. Magnetic resonance imaging of focal liver lesions: approach to imaging diagnosis. Hepatology 2011; 54: 2227-2237
• 29 Maccioni F, Martinelli M, Al Ansari N. et al. Magnetic resonance cholangiography: past, present and future: a review. Eur Rev Med Pharmacol Sci 2010; 14: 721-725
• 30 Zhang H, Zhu J, Ke F. et al. Radiological imaging for assessing the respectability of hilar cholangiocarcinoma: a systematic review and meta-analysis. Biomed Res Int 2015; 2015: 497942
• 31 Liu R, Cox Rn K, Siddiqui A. et al. Peroral cholangioscopy facilitates targeted tissue acquisition in patients with suspected cholangiocarcinoma. Minerva Gastroenterol Dietol 2014; 60: 127-133
• 32 Tischendorf JJ, Kruger M, Trautwein C. et al. Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Endoscopy 2006; 38: 665-669
• 33 Voigtlander T, Lankisch TO. Endoscopic diagnosis of cholangiocarcinoma: From endoscopic retrograde cholangiography to bile proteomics. Best Pract Res Clin Gastroenterol 2015; 29: 267-275
• 34 Navaneethan U, Njei B, Lourdusamy V. et al. Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of malignant biliary strictures: a systematic review and meta-analysis. Gastrointest Endosc 2015; 81: 168-176
• 35 Navaneethan U, Singh T, Gutierrez NG. et al. Predictors for detection of cancer in patients with indeterminate biliary stricture and atypical cells on endoscopic retrograde brush cytology. J Dig Dis 2014; 15: 268-275
• 36 Charatcharoenwitthaya P, Enders FB, Halling KC. et al. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008; 48: 1106-1117
• 37 Furmanczyk PS, Grieco VS, Agoff SN. Biliary brush cytology and the detection of cholangiocarcinoma in primary sclerosing cholangitis: evaluation of specific cytomorphologic features and CA19-9 levels. Am J Clin Pathol 2005; 124: 355-360
• 38 Lankisch TO, Metzger J, Negm AA. et al. Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis. Hepatology 2011; 53: 875-884
• 39 Metzger J, Negm AA, Plentz RR. et al. Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders. Gut 2013; 62: 122-130
• 40 Chapman R, Fevery J, Kalloo A. et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 51: 660-678
• 41 Bridgewater J, Galle PR, Khan SA. et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014; 60: 1268-1289
• 42 Broome U, Olsson R, Loof L. et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996; 38: 610-615
• 43 Melum E, Karlsen TH, Schrumpf E. et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology 2008; 47: 90-96
• 44 Bergquist A, Glaumann H, Persson B. et al. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998; 27: 311-316
• 45 Khuntikeo N, Chamadol N, Yongvanit P. et al. Cohort profile: cholangiocarcinoma screening and care program (CASCAP). BMC Cancer 2015; 15: 459
• 46 Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology 2008; 48: 308-321
• 47 Schweitzer N, Weber T, Kirstein MM. et al. The effect of adjuvant chemotherapy in patients with intrahepatic cholangiocarcinoma: a matched pair analysis. J Cancer Res Clin Oncol 2017; 143: 1347-1355
• 48 Lamarca A, Hubner RA, David Ryder W. et al. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol 2014; 25: 2328-2338
• 49 Edeline J, Bonnetain F, Phelip JM. et al. Gemox versus surveillance following surgery of localized biliary tract cancer: Results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial. J Clin Oncol 2017; 35 (Suppl) 225 doi:10.1200/JCO.2017.35.4_suppl.225
• 50 Primrose JN, Fox R, Palmer DH. et al. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. J Clin Oncol 2017; 34 (Suppl) Abstr. 4006
• 51 Pitt HA, Nakeeb A, Abrams RA. et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 1995; 221: 788-797 discussion 797–788
• 52 Vern-Gross TZ, Shivnani AT, Chen K. et al. Survival outcomes in resected extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a surveillance, epidemiology, and end results analysis. Int J Radiat Oncol Biol Phys 2011; 81: 189-198
• 53 Horgan AM, Amir E, Walter T. et al. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 2012; 30: 1934-1940
• 54 Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96: 896-902
• 55 Sasaki T, Isayama H, Nakai Y. et al. A randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine monotherapy for advanced biliary tract cancer. Cancer Chemother Pharmacol 2013; 71: 973-979
• 56 Kim RD, McDonough SL, El-Khoueiry AB. et al. SWOG S1310: Randomized phase II trial of single agent MEK inhibitor trametinib vs. 5-fluorouracil or capecitabine in refractory advanced biliary cancer. J Clin Oncol 2017; 35 (Suppl) 4016-4016
• 57 Pape UF, Kasper S, Sinn M. et al. Randomized, multicenter phase II trial of CAP7.1 in patients with advanced biliary tract cancers. J Clin Oncol 2016; 34 (Suppl) 441-441
• 58 Lee J, Park SH, Chang HM. et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012; 13: 181-188
• 59 Bekaii-Saab T, Phelps MA, Li X. et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol 2011; 29: 2357-2363
• 60 Lowery MA, Abou-Alfa GK, Valle JW. et al. ClarIDHy: A phase 3, multicenter, randomized, double-blind study of AG-120 vs. placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation. J Clin Oncol 2017; 35 (Suppl) TPS4142 [Epub ahead of print]
• 61 Mazzaferro V, El-Rayes BF, Cotsoglou C. et al. ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations. J Clin Oncol 2017; 35 (Suppl) 4017-4017