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| __NOTOC__ | | __NOTOC__ |
| {{Cholangiocarcinoma}} | | {{Cholangiocarcinoma}} |
| {{CMG}} | | {{CMG}};{{AE}} {{F.K}}, {{PSK}} |
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| ==Overview== | | ==Overview== |
| | Chemotherapy is indicated for unresectable cholangiocarcinoma as [[palliation|palliative chemotherapy]]. Chemotherapy agents used to treat cholangiocarcinoma include [[5-fluorouracil]], [[gemcitabine]], [[irinotecan]], [[cisplatin]], or [[doxorubicin]]. |
| | ==Medical Therapy== |
| | The majority of cases of cholangiocarcinoma present as unresectable disease.<ref>{{cite journal |author=Vauthey J, Blumgart L |title=Recent advances in the management of cholangiocarcinomas |journal=Semin. Liver Dis. |volume=14 |issue=2 |pages=109-14 |year=1994 |pmid=8047893}}</ref> If the tumor cannot be surgically removed, patients are often treated with [[palliation|palliative]] [[chemotherapy]] with or without [[radiotherapy]]. |
| | ===Chemotherapy=== |
| | * 1.'''Chemotherapy''' |
| | ** Preferred regimen (1): [[5-fluorouracil]] 600 mg/m2 with [[leucovorin]] 400 mg/m2 over 2 hours once every 2 weeks <ref name="pmid23919111">{{cite journal |vauthors=Ramírez-Merino N, Aix SP, Cortés-Funes H |title=Chemotherapy for cholangiocarcinoma: An update |journal=World J Gastrointest Oncol |volume=5 |issue=7 |pages=171–6 |year=2013 |pmid=23919111 |pmc=3731530 |doi=10.4251/wjgo.v5.i7.171 |url=}}</ref> |
| | ** Alternative regimen (2): [[Gemcitabine]] 1,000 mg/m2 plus cisplatin <ref name="pmid15800324">{{cite journal |vauthors=Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E, Nematollahi M, Pond GR, Zhang J, Moore MJ |title=Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial |journal=J. Clin. Oncol. |volume=23 |issue=10 |pages=2332–8 |year=2005 |pmid=15800324 |doi=10.1200/JCO.2005.51.008 |url=}}</ref> |
| | ** Alternative regimen (3): [[Irinotecan]] 125 mg/m2 q14 days |
| | ** Alternative regimen (4): [[Oxaliplatin]] 400 mg/m2 <ref name="pmid15319238">{{cite journal |vauthors=André T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, Avenin D, Selle F, Paye F, Hannoun L, Houry S, Gayet B, Lotz JP, de Gramont A, Louvet C |title=Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study |journal=Ann. Oncol. |volume=15 |issue=9 |pages=1339–43 |year=2004 |pmid=15319238 |doi=10.1093/annonc/mdh351 |url=}}</ref> |
| | ** Alternative regimen (5): [[Doxorubicin]] 60-75 mg/m2 q21 days <ref name="pmid11705850">{{cite journal |vauthors=Patt YZ, Hassan MM, Lozano RD, Waugh KA, Hoque AM, Frome AI, Lahoti S, Ellis L, Vauthey JN, Curley SA, Schnirer II, Raijman I |title=Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer |journal=Clin. Cancer Res. |volume=7 |issue=11 |pages=3375–80 |year=2001 |pmid=11705850 |doi= |url=}}</ref> |
| | ** Alternative regimen (6): [[Capecitabine]] 650 mg/m2 q21 days for 2 weeks |
| | ** Alternative regimen (7): [[Erlotinib]] PO 100 mg/day |
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| ==Adjuvant Chemotherapy and Radiation Therapy== | | ===Regional therapies=== |
| The options for the treatment of CCA are limited and associated with high rates of perioperative mortality, recurrence, and short survival times. Surgical resection of tumors with negative margins is the best option for all subtypes of CCA, although it is only achieved in less than 50% of cases, and it is often necessary to perform a partial hepatectomy together with the removal of regional lymph nodes. Curative resection, or resection of tumor-free surgical margins (R0), remains the best chance for long-term survival, and lymph node status is the most important prognostic factor following R0 resection [17]. Routine lymphadenectomy at the time of surgical resection has been proposed in order to increase the chance of survival; however it can be omitted in patients with solitary, small peripheral CCA because the probability of lymph node metastasis is very low [66].
| | *Regional therapies is recommended among patients with small cholangiocarcinomas, when the general health condition of the patient does not allow a more aggressive treatment:<ref name="pmid22627601">{{cite journal |vauthors=Halappa VG, Bonekamp S, Corona-Villalobos CP, Li Z, Mensa M, Reyes D, Eng J, Bhagat N, Pawlik TM, Geschwind JF, Kamel IR |title=Intrahepatic cholangiocarcinoma treated with local-regional therapy: quantitative volumetric apparent diffusion coefficient maps for assessment of tumor response |journal=Radiology |volume=264 |issue=1 |pages=285–94 |year=2012 |pmid=22627601 |doi=10.1148/radiol.12112142 |url=}}</ref><ref name="pmid21460876">{{cite journal |vauthors=Patel T |title=Cholangiocarcinoma--controversies and challenges |journal=Nat Rev Gastroenterol Hepatol |volume=8 |issue=4 |pages=189–200 |year=2011 |pmid=21460876 |pmc=3888819 |doi=10.1038/nrgastro.2011.20 |url=}}</ref> |
| | | **[[Transcatheter arterial chemoembolization|Transarterial chemoembolization]] ([[Transcatheter arterial chemoembolization|TACE]]) |
| In iCCAs, resection has usually been indicated in patients with a solitary tumor and with no underlying hepatic disease. The best prognostic factors are R0 resection without lymph node invasion, while tumor diameter, histology, and differentiation are poor predictors of good outcome. The 5-year survival rates reported in the past few years vary from 20 to 60% [17]. A recent study has concluded that major hepatectomy for iCCA is also indicated in selected cirrhotic patients because the overall morbidity, hospital mortality rates, and the appearance of liver failure and other complications (superficial wound infection, abscesses, sepsis, pancreatic leakage, delayed gastric emptying, or biliary leakage) are similar in patients with and without cirrhosis [67].
| | **[[Therapeutic embolization|Radioembolization]] |
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| Resection is a suitable treatment option for extrahepatic tumors, depending on the extent in the biliary tree and hepatic vasculature. When such tumors are restricted to one lobe, there is no metastasis, and liver function is preserved, resection is recommended. Partial hepatectomy is the only factor associated with better outcome, probably because this option permits negative margins to be achieved. The 5-year survival for R0-resected eCCAs is about 30% [17], with recurrence observed in the majority of patients due to disseminated tumors or the de novo formation of tumors in the already oncogenic liver tissue. Thus, surgical resection is not recommended for CCAs in patients with primary sclerosing cholangitis because the recurrence rate is very high, close to 90%.
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| Liver transplantation is usually recommended for patients with pCCA diagnosed in the early stages, which cannot be removed surgically, and when no metastases are detected [68] and also for patients with tumors developed in livers with reduced function or underlying a biliary inflammation pathology, such as primary sclerosing cholangitis. Liver transplantation performed after neoadjuvant chemoradiation in selected patients, due to organ shortage, has afforded a very good disease-free 5-year survival (>80%), providing a better outcome and fewer recurrences than conventional resection [69, 70].
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| Tumor ablation performed percutaneously with sonographic guidance using radiofrequency or microwave energy can offer efficient therapy for nonoperable tumors up to 5 cm in size. Complete tumor destruction without local recurrence was reached in 85% of patients with iCCA, with a median overall survival period of 38.5 months, while major complications occurred in 6% of the cases [71].
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| The currently available adjuvant therapies, chemotherapy, and radiotherapy have not been shown to improve the outcome or time to recurrence of patients when administered either before or after surgery, although no large randomized trials have been conducted. It has even been reported that radiation therapy may elicit unwanted results, such as difficulties in handling cholangiopathies [4].
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| Palliative chemotherapy, radiotherapy, and photodynamic therapy have been relatively ineffective in treating non-operable CCAs, with a 5-year survival <5% without resection, due to the refractoriness of these tumors.
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| For some patients with non-operable tumors, biliary drainage through a tiny metal or plastic tube (‘‘biliary stent’’) may result in an improvement of the patient’s situation due to relief of the obstructive cholestasis. This can be done percutaneously, although with these external drainage systems patients may experience certain discomfort, and it is the only option in cases of complete biliary obstruction. Stents may eventually cease to function because of tumor overgrowth, obstruction, or other reasons; plastic stents need to be changed every 3 months, while metal stents can be maintained for longer times [72]. Cholestasis is a risk factor for hepatic failure after liver resection and stents are now widely used for preoperative drainage. Self-expanding metal stents are preferred because they provide rapid biliary decompression and a reduced complication rate after insertion [73].
| | ===Photodynamic Therapy=== |
| | | *[[Photodynamic therapy]] |
| Evaluation of the clinical usefulness of other therapeutical strategies that have emerged in recent years requires further investigation. Thus, photodynamic therapy seems to relieve pain, improves the flow of bile through the biliary tree, and increases survival.
| | **Injected with a light-sensitizing agent and light is then applied [[endoscopy|endoscopically]] directly to the tumor <ref>{{cite journal |author=Ortner M, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, Voderholzer W, Schachschal G, Mössner J, Lochs H |title=Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study |journal=Gastroenterology |volume=125 |issue=5 |pages=1355–63 |year=2003 |pmid=14598251}}</ref><ref>{{cite journal |author=Zoepf T, Jakobs R, Arnold J, Apel D, Riemann J |title=Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy |journal=Am J Gastroenterol |volume=100 |issue=11 |pages=2426–30 |year=2005 |pmid=16279895}}</ref> |
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| Transarterial chemoembolization (TACE), which increases the local concentration of chemotherapeutic agents and reduces systemic exposure [74], has shown promising results, increasing survival [75], and radioembolization [76] also seems to increase survival. Thus, these regional therapies are considered as an option for treating small tumors when the general health condition of the patient does not permit a more aggressive treatment.
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| An important number of phase-II clinical trials have been carried out with different chemotherapy regimes to treat CCA, using single or combined agents (Table 5). In contrast, to date the number of phase-III trials has been low. These studies have some limitations, mainly due to the heterogeneity of the tumor types included (grouped as biliary tract cancer in some studies, or CCA without separation between types), different extents of the disease, naïve patients mixed together with patients who have previously received different therapies, small numbers of patients included, and so forth. This has contributed to the fact that, even though the moderate benefits and tolerability of some regimes have been described, as commented below, no standard treatment for CCA has yet been established.
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| If the tumor can be removed surgically, patients may receive [[adjuvant#oncology|adjuvant]] [[chemotherapy]] or [[radiation therapy]] after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally [[excision|excised]]), adjuvant therapy is of uncertain benefit. Both positive<ref>{{cite journal |author=Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H, Otsuka M, Fukao K |title=Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma |journal=Int J Radiat Oncol Biol Phys |volume=46 |issue=3 |pages=581-7 |year=2000 |pmid=10701737}}</ref><ref>{{cite journal |author=Alden M, Mohiuddin M |title=The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer |journal=Int J Radiat Oncol Biol Phys |volume=28 |issue=4 |pages=945-51 |year=1994 |pmid=8138448}}</ref> and negative<ref>{{cite journal |author=González González D, Gouma D, Rauws E, van Gulik T, Bosma A, Koedooder C |title=Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma |journal=Ann Oncol |volume=10 Suppl 4 |issue= |pages=215-20 |year= |pmid=10436826}}</ref><ref>{{cite journal |author=Pitt H, Nakeeb A, Abrams R, Coleman J, Piantadosi S, Yeo C, Lillemore K, Cameron J |title=Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival |journal=Ann Surg |volume=221 |issue=6 |pages=788–97; discussion 797-8 |year=1995 |pmid=7794082}}</ref> results have been reported with adjuvant radiation therapy in this setting, and no prospective [[randomized controlled trial]]s have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in patients with completely resected tumors.<ref>{{cite journal |author=Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, Nagakawa T, Nakayama T |title=Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma |journal=Cancer |volume=95 |issue=8 |pages=1685–95 |year=2002 |pmid=12365016}}</ref> The role of combined chemoradiotherapy in this setting is unclear. However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended based on the available data.<ref name="nccn">{{PDFlink|[http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf National Comprehensive Cancer Network (NCCN) guidelines on evaluation and treatment of hepatobiliary malignancies]|216 [[Kibibyte|KiB]]<!-- application/pdf, 221777 bytes -->}}. Accessed [[March 13]] [[2007]].</ref>
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| ==Treatment of Advanced Disease==
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| ====Chemotherapy====
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| The majority of cases of cholangiocarcinoma present as unresectable disease.<ref>{{cite journal |author=Vauthey J, Blumgart L |title=Recent advances in the management of cholangiocarcinomas |journal=Semin. Liver Dis. |volume=14 |issue=2 |pages=109-14 |year=1994 |pmid=8047893}}</ref> If the tumor cannot be surgically removed, patients are often treated with [[palliation|palliative]] [[chemotherapy]] with or without [[radiotherapy]]. Chemotherapy has been shown in a [[randomized controlled trial]] to improve [[quality of life]] and extend survival in patients with inoperable cholangiocarcinoma.<ref>{{cite journal |author=Glimelius B, Hoffman K, Sjödén P, Jacobsson G, Sellström H, Enander L, Linné T, Svensson C |title=Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer |journal=Ann Oncol |volume=7 |issue=6 |pages=593–600 |year=1996 |id=PMID 8879373}}</ref> There is no single chemotherapy regimen which is universally used, and enrollment in [[clinical trial]]s is often recommended when possible.<ref name="nccn"/> Chemotherapy agents used to treat cholangiocarcinoma include [[5-fluorouracil]] with [[leucovorin]],<ref>{{cite journal |author=Choi C, Choi I, Seo J, Kim B, Kim J, Kim C, Um S, Kim J, Kim Y |title=Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas |journal=Am J Clin Oncol |volume=23 |issue=4 |pages=425-8 |year=2000 |pmid=10955877}}</ref> [[gemcitabine]] as a single agent,<ref>{{cite journal |author=Park J, Oh S, Kim S, Kwon H, Kim J, Jin-Kim H, Kim Y |title=Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study |journal=Jpn J Clin Oncol |volume=35 |issue=2 |pages=68–73 |year=2005 |pmid=15709089}}</ref> or gemcitabine plus [[cisplatin]],<ref>{{cite journal |author=Giuliani F, Gebbia V, Maiello E, Borsellino N, Bajardi E, Colucci G |title=Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM) |journal=Ann Oncol |volume=17 Suppl 7 |issue= |pages=vii73-vii77 |year= |pmid=16760299}}</ref> [[irinotecan]],<ref>{{cite journal |author=Bhargava P, Jani C, Savarese D, O'Donnell J, Stuart K, Rocha Lima C |title=Gemcitabine and irinotecan in locally advanced or metastatic biliary cancer: preliminary report |journal=Oncology (Williston Park) |volume=17 |issue=9 Suppl 8 |pages=23-6 |year=2003 |pmid=14569844}}</ref> or [[capecitabine]].<ref>{{cite journal |author=Knox J, Hedley D, Oza A, Feld R, Siu L, Chen E, Nematollahi M, Pond G, Zhang J, Moore M |title=Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial |journal=J Clin Oncol |volume=23 |issue=10 |pages=2332–8 |year=2005 |pmid=15800324}}</ref> A small pilot study suggested possible benefit from the [[tyrosine kinase]] inhibitor [[erlotinib]] in patients with advanced cholangiocarcinoma.<ref>{{cite journal |author=Philip P, Mahoney M, Allmer C, Thomas J, Pitot H, Kim G, Donehower R, Fitch T, Picus J, Erlichman C |title=Phase II study of erlotinib in patients with advanced biliary cancer |journal=J Clin Oncol |volume=24 |issue=19 |pages=3069–74 |year=2006 |pmid=16809731}}</ref>
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| ====Photodynamic Therapy====
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| [[Photodynamic therapy]], an experimental approach in which patients are injected with a light-sensitizing agent and light is then applied [[endoscopy|endoscopically]] directly to the tumor, has shown promising results compared to supportive care in two small [[randomized controlled trial]]s. However, its ultimate role in the management of cholangiocarcinoma is unclear at present.<ref>{{cite journal |author=Ortner M, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, Voderholzer W, Schachschal G, Mössner J, Lochs H |title=Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study |journal=Gastroenterology |volume=125 |issue=5 |pages=1355–63 |year=2003 |pmid=14598251}}</ref><ref>{{cite journal |author=Zoepf T, Jakobs R, Arnold J, Apel D, Riemann J |title=Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy |journal=Am J Gastroenterol |volume=100 |issue=11 |pages=2426–30 |year=2005 |pmid=16279895}}</ref> | |
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| ==References== | | ==References== |
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| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |
| | [[Category:Up-To-Date]] |
| | [[Category:Oncology]] |
| | [[Category:Medicine]] |
| | [[Category:Gastroenterology]] |
| | [[Category:Surgery]] |