Palliation of unresectable cholangiocarcinoma: can we do more than merely drain?

Oncologically radical surgical resection (R0) is the only chance of cure for perihilar and distal cholangiocarcinomas with 5-year survival rates of 25 % – 50 % and 70 %, respectively [1] [2]. Orthotopic liver transplantation (OLT) in patients with unresectable perihilar cholangiocarcinoma is also performed with curative intent, but in only a few centers around the world [3]. While surgical resection is the favored surgical treatment modality, OLT might be preferred in patients with cholangiocarcinoma occurring in the setting of primary sclerosing cholangitis (PSC), because of the limited hepatic reserves and the risk of recurrent cholangiocarcinoma in the liver remnant. In patients in whom resectability is restricted by the risk of hepatic failure because of the small volume of the hepatic remnant, preoperative portal vein embolization of the hemiliver that will be resected to induce hypertrophy of the contralateral hemiliver may be practiced [4]. Unfortunately, the vast majority of patients with perihilar cholangiocarcinoma are inoperable and/or unresectable at the time of diagnosis because of extensive local biliary and vascular invasion or, less frequently, distant metastases. The typical clinical presentation includes progressive cholestasis, itching, jaundice, and, more rarely, recurrent cholangitis resulting from progressive biliary obstruction due to the tumor’s growth along the biliary tree. Obstructive biliary symptoms usually require a palliative treatment, which is aimed at improving quality of life and prolonging survival. The mainstay of palliative treatment in this setting is biliary drainage, which may be obtained surgically, endoscopically, or via the percutaneous transhepatic route (or by a combination of the last two approaches). Surgical palliation has lost much of its importance in the last three decades thanks to the development of less invasive techniques such as endoscopy and interventional radiology. However, palliative surgical resection might still have a role in patients who are fit for surgery, because of better results in terms of survival [5], which reflect the long natural history of these tumors. Palliation is currently obtained mainly by endoscopic or percutaneous transhepatic placement of self-expandable metal stents (SEMSs). SEMSs have shown better results in terms of long-term efficacy compared with plastic stents in randomized controlled trials, also in the setting of perihilar malignant strictures [6]. In patients with complex perihilar cholangiocarcinoma, involving the main hepatic confluence, only uncovered SEMSs should be used in order to avoid potential septic complications due to the blockage of intrahepatic biliary radicles by covered stents. In contrast, it is still unclear how much hepatic parenchyma should be drained to achieve the best palliation. The current tendency is to drain as much as possible, and, when feasible, to obtain a complete drainage of the intrahepatic branches, even in complex strictures, by placement of multiple SEMSs, either side by side or in a Y shape. In fact, because of the long natural history of these tumors, which have a low propensity to metastasize, septic complications due to bile infection in undrained segments represent a major cause of death before the tumor itself has disseminated. Adequate biliary drainage therefore seems to be the pillar of palliative treatment in perihilar cholangiocarcinoma. However, can we do more than merely drain? Mukewar et al. [7] herein report on the use of endoscopically delivered high dose-rate (HDR) brachytherapy as part of neoadjuvant therapy for unresectable perihilar cholangiocarcinoma in patients who were candidates for OLT: 40 patients were included in a treatment protocol with curative intent that comprised external beam radiotherapy (EBRT), chemotherapy, and HDR brachytherapy, eventually followed by OLT. This experience shows that HDR brachytherapy delivered via endoscopically inserted nasobiliary drains is feasible with a reasonable rate of occurrence of adverse events. The question is whether HDR brachytherapy might be useful not only in the setting of a curative intent protocol before OLT, but also as an adjunct to drainage in a palliative scenario. Intraluminal brachytherapy (ILBT) – whether HDR or low dose rate (LDR) – is one of the ablative therapies that can be performed in the bile ducts either endoscopically or percutaneously. This treatment modality is frequently used in conjunction with EBRT. Our group demonstrated the feasibility and safety of LDR brachytherapy with 192Iridium way back in 1995 [8]. Unfortunately, since then, no prospective comparative trials have been performed. Even if some retrospective studies [9] comparing ILBT, with or without EBRT, to historical controls have shown a superiority of the active treatment, the evidence that ILBT is useful in prolonging survival remains of very low quality. Furthermore, the positive results of ILBT/EBRT should also be weighted against acute and late toxicity, such as gastrointestinal erosions and ulceration. The feasibility and safety of endoscopically delivered HDR brachytherapy has also been recently reported by our group as an adjunct to SEMS placement for the palliation of unresectable cholangiocarcinoma [10]. Photodynamic therapy is another ablative technique, which has been used for several years [11]. Photodynamic therapy involves the intravenous injection of a photosensitizer, which accumulates preferentially into the neoplastic cells. The target tissue is later exposed to a light of appropriate photoactivating wavelength, which is generated by a laser fiber introduced endoscopically or percutaneously. The induced photochemical reaction generates the formation of cytotoxic reactive oxygen species that eventually produce tumor necrosis. Despite several published experiences, the evidence in favor of this technique remains low owing to the lack of an adequate number of randomized controlled trials [12]. Recently, another ablation technique has been added to the armamentarium: endobiliary radiofrequency delivery. Radiofrequency ablation has been largely utilized in different solid neoplastic lesions, especially in the liver, but only in recent years, thanks to the development of specialized probes, has it been possible for this ablation modality to be applied within the bile ducts. Radiofrequency induces thermal injury and subsequent localized necrosis of the targeted tissue. The technique is cheap, easy to perform, and seems safe when applied in the extrahepatic bile duct [13]. However, it should be used with caution in the intrahepatic ducts because of the risk of delayed bleeding due to vascular injury of the portal or arterial branches, which run parallel to the bile duct. The evidence in favor of radiofrequency ablation is once again very low because of the lack of prospective randomized trials. In conclusion, given that the efficacy of drainage is a major factor in the quality of life and length of survival of patients with advanced unresectable cholangiocarcinoma, over and above the effects of these techniques on the tumor’s biology, it seems logical to add an ablation procedure to stenting alone; however, this paradigm should be validated by prospective randomized trials, which are at the moment not available.