Gatto M, Alvaro D (2010) New insights on cholangiocarcinoma. World J Gastrointest Oncol, 2(3):136-145
Introduction
CCA is characterized by a bad prognosis, with a median survival of less than 24 mo[2-4] and a scarce response to chemotherapy[5-9] The only curative therapy is surgical resection or liver transplantation but, unfortunately, the majority of patients are diagnosed at advanced stage, when surgical therapies are excluded. This should stimulate research on the identification of effective surveillance strategies that would permit detection of early CCA or, better yet, premalignant lesions in patients at increased risk, particularly patients with primary sclerosing cholangitis (PSC). Serum and bile tumor markers, non invasive and endoscopic-based imaging modalities, and histology and cytology have been attempted with varying success[11].
Epidemiology
Hepatobiliary malignancies account for 13% of the 7.6 million annual cancer-related deaths worldwide and for 3% of the 560 000 annual cancer-related deaths in the United States. CCA accounts for 10% to 20% of he deaths from hepatobiliary malignancies. The prevalence of CCA shows a wide geographical variability, with the highest rates in Asia and the lowest in Australia[14]. In the United States, the incidence of CCA has been reported to be 0.95/100 000 for IH-CCA and 0.82/100 000 for EH-CCA[14,15] A number of recent studies have highlighted a progressive increase, in the past three decades, in the mortality for IH-CCA[15] , while EHCCA mortality is stable or slightly decreasing[12,15]
Very recently, data on the mortality and incidence trend for CCA have also been reported in Italy, where a 40-fold increase in mortality for IH-CCA has been documented from 1980 to 2003. For EH-CCA, in contrast, mortality rates were stable or slightly decreasing in the last 10 years. Thus, as described in most countries, in Italy the increased mortality for CCA mainly involves the intrahepatic form, suggesting different etiology and risk factors for IH- and EH-CCA[14-16]. Interestingly, in all epidemiological studies concerning
primary liver malignancies, a high percentage (about 40%) of primitive liver cancers are classified as adenocarcinoma and are therefore excluded from the group of either CCA or hepatocellular carcinoma. This probably accounts for a significant underscoring of IH-CCA incidence and mortality because it is a common clinical opinion that most primary liver adenocarcinomas are indeed CCA[21]. Biological, immunohistochemical, or genetic markers[4,21] could definitively permit an exact diagnosis and classification of primary liver cancers and avoid these classification biases.
Serum and Bile biomarkers aiding CCA diagnosis
On the basis of test properties, cost and availability, combination of serum CA 19-9 (cut-off value of 20 U/mL) and abdominal US at 12-mo intervals was proposed as a useful strategy for the screening/surveillance of CCA in PSC[10,100].
Treatment
There is no current effective medical therapy for CCA, and the median survival after treatment of unresectable disease is 9-12 mo[122,123]. Complete operative resection might be curative, but local extension of the disease often precludes complete resection[124,125].
Solitary IH-CCAs are managed by segmentectomy or lobectomy. Five-year survival rates are 22%-44% and correlate with R0 (negative margin) resection, absence of lymph node metastases, and vascular invasion[126-130]. Even with complete resection, local recurrence is common, with most series reporting five-year survival of 25%-35%.
Survival analysis of patients treated according to the Mayo Clinic protocol has yielded one-and five-year survival rates of 91% and 76%, respectively[136,137].
In these studies, PDT alone, or plus stenting, improved cholestasis and quality of life considerably, and had a favourable side-effect profile. In the light of these findings, recent review articles recommended PDT for patients with not resectable disease[140].
As far as pharmacological therapy is concerned, CCA is characterized by a remarkable resistance to common chemotherapy[122,123]. Several drugs have been tested alone in unresectable CCA and in restricted phase Ⅱ studies (5-FU, methanesulfon-m-anisidide, cisplatin, rifampicin, mitomycin C, paclitaxel, and gemcitabine) with partial response of 0%-9% and average survival of 2-12 mo. With regard to combination therapies, one of the most used therapeutic plans is ECF (epirubicin + cisplatin + 5-FU), but with disappointing results[143].
Paucity of data makes it impossible to use adjuvant chemotherapy after surgical resection[152]. In particular, chemotherapy with 5-FU and mitomycin C failed to improve the survival of patients undergoing surgical resection, as recently observed in a phase Ⅲ study[153].
Introduction
CCA is characterized by a bad prognosis, with a median survival of less than 24 mo[2-4] and a scarce response to chemotherapy[5-9] The only curative therapy is surgical resection or liver transplantation but, unfortunately, the majority of patients are diagnosed at advanced stage, when surgical therapies are excluded. This should stimulate research on the identification of effective surveillance strategies that would permit detection of early CCA or, better yet, premalignant lesions in patients at increased risk, particularly patients with primary sclerosing cholangitis (PSC). Serum and bile tumor markers, non invasive and endoscopic-based imaging modalities, and histology and cytology have been attempted with varying success[11].
Epidemiology
Hepatobiliary malignancies account for 13% of the 7.6 million annual cancer-related deaths worldwide and for 3% of the 560 000 annual cancer-related deaths in the United States. CCA accounts for 10% to 20% of he deaths from hepatobiliary malignancies. The prevalence of CCA shows a wide geographical variability, with the highest rates in Asia and the lowest in Australia[14]. In the United States, the incidence of CCA has been reported to be 0.95/100 000 for IH-CCA and 0.82/100 000 for EH-CCA[14,15] A number of recent studies have highlighted a progressive increase, in the past three decades, in the mortality for IH-CCA[15] , while EHCCA mortality is stable or slightly decreasing[12,15]
Very recently, data on the mortality and incidence trend for CCA have also been reported in Italy, where a 40-fold increase in mortality for IH-CCA has been documented from 1980 to 2003. For EH-CCA, in contrast, mortality rates were stable or slightly decreasing in the last 10 years. Thus, as described in most countries, in Italy the increased mortality for CCA mainly involves the intrahepatic form, suggesting different etiology and risk factors for IH- and EH-CCA[14-16]. Interestingly, in all epidemiological studies concerning
primary liver malignancies, a high percentage (about 40%) of primitive liver cancers are classified as adenocarcinoma and are therefore excluded from the group of either CCA or hepatocellular carcinoma. This probably accounts for a significant underscoring of IH-CCA incidence and mortality because it is a common clinical opinion that most primary liver adenocarcinomas are indeed CCA[21]. Biological, immunohistochemical, or genetic markers[4,21] could definitively permit an exact diagnosis and classification of primary liver cancers and avoid these classification biases.
Serum and Bile biomarkers aiding CCA diagnosis
On the basis of test properties, cost and availability, combination of serum CA 19-9 (cut-off value of 20 U/mL) and abdominal US at 12-mo intervals was proposed as a useful strategy for the screening/surveillance of CCA in PSC[10,100].
Treatment
There is no current effective medical therapy for CCA, and the median survival after treatment of unresectable disease is 9-12 mo[122,123]. Complete operative resection might be curative, but local extension of the disease often precludes complete resection[124,125].
Solitary IH-CCAs are managed by segmentectomy or lobectomy. Five-year survival rates are 22%-44% and correlate with R0 (negative margin) resection, absence of lymph node metastases, and vascular invasion[126-130]. Even with complete resection, local recurrence is common, with most series reporting five-year survival of 25%-35%.
Survival analysis of patients treated according to the Mayo Clinic protocol has yielded one-and five-year survival rates of 91% and 76%, respectively[136,137].
In these studies, PDT alone, or plus stenting, improved cholestasis and quality of life considerably, and had a favourable side-effect profile. In the light of these findings, recent review articles recommended PDT for patients with not resectable disease[140].
As far as pharmacological therapy is concerned, CCA is characterized by a remarkable resistance to common chemotherapy[122,123]. Several drugs have been tested alone in unresectable CCA and in restricted phase Ⅱ studies (5-FU, methanesulfon-m-anisidide, cisplatin, rifampicin, mitomycin C, paclitaxel, and gemcitabine) with partial response of 0%-9% and average survival of 2-12 mo. With regard to combination therapies, one of the most used therapeutic plans is ECF (epirubicin + cisplatin + 5-FU), but with disappointing results[143].
Paucity of data makes it impossible to use adjuvant chemotherapy after surgical resection[152]. In particular, chemotherapy with 5-FU and mitomycin C failed to improve the survival of patients undergoing surgical resection, as recently observed in a phase Ⅲ study[153].
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