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Advanced hilar cholangiocarcinoma: An aggressive surgical approach for the treatment of advanced hilar cholangiocarcinoma: Perioperative management, extended procedures, and multidisciplinary approaches
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Advanced hilar cholangiocarcinoma: An aggressive surgical approach for the treatment of advanced hilar cholangiocarcinoma: Perioperative management, extended procedures, and multidisciplinary approaches Takashi Mizuno∗, Tomoki Ebata, Masato Nagino Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
ARTICLE INFO
ABSTRACT
Keywords: Perihilar cholangiocarcinoma Vascular reconstruction Hepatopancreaticoduodenectomy
Hilar cholangiocarcinoma is a highly intractable malignancy. One of the reasons for its intractability is that most patients with the disease are diagnosed with an advanced stage of the disease at their initial presentation. Surgical resection is the standard therapy for hilar cholangiocarcinoma, providing a chance for a cure, and an aggressive surgical approach substantially increases the number of resectable tumors that are initially regarded as unresectable tumors. The success and standardization of the aggressive approach is warranted by meticulous preoperative management that prevents fatal postoperative complications. Extended resection procedures, including hepatic trisectionectomy for Bismuth type IV tumors, hepatopancreaticoduodenectomy for tumors with extensive longitudinal tumor spreading, and combined vascular resection with reconstruction for tumors with the involvement of hepatic vascular structures, have been challenged to expand the surgical indication. Due to acceptable surgical/survival outcomes, the three extended procedures are currently regarded as extended but standard options in specialized hepatobiliary centers. Although it remains a controversial multidisciplinary approach, the combination of these extended procedures with an adjuvant/neoadjuvant treatment is a promising approach for further improving the resectability of tumors and the survival of patients.
1. Introduction Hilar cholangiocarcinoma is a highly intractable malignancy. One of the reasons for the intractability is that most patients with the disease are diagnosed with advanced disease at their initial presentation. Advancements in nonsurgical treatments have prolonged the overall survival in patients with metastatic/locally unresectable tumors [1]; however, surgical resection undoubtedly remains the standard therapy for hilar cholangiocarcinoma, providing a chance for a cure. Refinements in surgical techniques and perioperative management over the past two decades have not only improved surgical/survival outcomes after resection but also expanded the indication for surgery. In addition, several extended resection procedures have also been attempted to treat advanced hilar cholangiocarcinoma, which was previously regarded as unresectable [2]. Furthermore, these extended procedures have been combined with adjuvant/neoadjuvant treatments for further improved overall survival, although this strategy remains controversial.
In this review article, the following three topics associated with aggressive surgical approaches were discussed: perioperative management, extended surgical procedures, and multidisciplinary approaches. Perioperative management was addressed first because meticulous perioperative management is crucial for the success of aggressive surgical approaches. Second, the three following extended resection procedures for various types of advanced hilar cholangiocarcinoma were discussed: hepatic trisectionectomy for Bismuth type IV tumors, hepatectomy with pancreaticoduodenectomy (HPD) for tumors with extensive longitudinal spreading and combined vascular resection with reconstruction for tumors involving adjacent vascular structures. Finally, multidisciplinary treatment strategies, including adjuvant therapy for resectable tumors and conversion therapy for initially unresectable tumors, were discussed because of increasing evidence in this field.
Abbreviations: HPD, hepatectomy with pancreaticoduodenectomy; PVR, combined resection with reconstruction of the portal vein; HAR, combined resection with reconstruction of the hepatic artery; HAPVR, combined simultaneous resection of the hepatic artery and portal vein ∗ Corresponding author. Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail address: [email protected] (T. Mizuno). https://doi.org/10.1016/j.suronc.2019.07.002 Received 27 May 2019; Received in revised form 27 June 2019; Accepted 7 July 2019 0960-7404/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Takashi Mizuno, Tomoki Ebata and Masato Nagino, Surgical Oncology, https://doi.org/10.1016/j.suronc.2019.07.002
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Fig. 1. Schematics and images of a) hepatic right trisectionectomy, b) hepatic left trisectionectomy, c) right hepatectomy with pancreaticoduodenectomy, and d) left trisectionectomy combined with simultaneous resection of the hepatic artery and portal vein. B2+3, left lateral sectoral bile duct; HA, hepatic artery; PV, portal vein; IVC, inferior vena cava; RHV, right hepatic vein; RPHD, right posterior hepatic duct; LHD, left hepatic duct; MHV, middle hepatic vein.
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2. Meticulous perioperative management for extended resection procedures
tumors with an increased chance of R0 resection and prolonged overall survival, and data from a Japanese multicenter retrospective study has indicated that the prognostic ability of the 7th edition staging system can be enhanced if the presence of Bismuth type IV tumors are removed from the T4 determinants [24]. In the newest 8th edition of the American Joint Committee on Cancer (AJCC) cancer staging manual, Bismuth type IV have been removed from the T4 category [25]. The revision suggests that these Bismuth type IV tumors are no longer contraindications for resection. Right trisectionectomy is less technically difficult than left trisectionectomy because of the presence of clear anatomical landmarks and a smaller hepatic transection surface [26]. Notably, anatomically extended right hepatic trisectionectomy should be performed to achieve a greater chance of a tumor-free ductal margin (Fig. 1a). The procedure is a completely different procedure from a classic right hepatic trisectionectomy because the proximal bile duct is cut at the left side of the umbilical portion of the portal vein [27]. Although right trisectionectomy is advantageous from the perspective of local tumor eradication, the smallest volume of a liver remnant risks posthepatectomy liver failure. Compared with right portal vein embolization alone, right portal vein embolization with segment 4 embolization is recommended to avoid posthepatectomy liver failure because it provides an increased rate of hypertrophy of a future liver remnant [28]. Recently, the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure has been enthusiastically introduced to more rapidly increase the volume of future liver remnants; however, this procedure for the treatment of hilar cholangiocarcinoma is discouraging due to extremely high mortality [29]. In contrast, left trisectionectomy is a much more technically demanding procedure because of an extensively wide hepatic transection surface and a lack of anatomical landmarks (Fig. 1b). [30] In addition, the right hepatic artery is more likely to be involved due to the anatomical vicinity between the artery and hilar bile ducts. Thus, resection with reconstruction of the right hepatic artery is likely to be combined with left trisectionectomy, which is discussed in a subsequent section.
Before discussing the aggressive surgical approach, details regarding perioperative management must be addressed because surgical outcomes depend on the quality of perioperative management in addition to surgical techniques. Nevertheless, the reported surgical outcomes after hilar cholangiocarcinoma surgery are inconsistent between tertiary hepatobiliary centers, with postoperative mortality ranging from 0 to 13% [2–4]. It is assumed that this inconsistency is partially attributed to differences in perioperative management between the centers. The most serious postoperative complication that is the main cause of 90-day mortality is posthepatectomy liver failure. To avoid fatal complications, patients should be treated with the following meticulous perioperative management strategies: precise evaluation of the functional capacity of the future liver remnant [5], aggressive use of preoperative portal vein embolization [6], and appropriate biliary drainage using endoscopic nasobiliary drainage [7]. Several analytical methods are available for the estimation of the functional capacity of future liver remnant [8–10]. Notably, background cholestatic liver is associated with decreased hepatic function even after biliary decompression, and major hepatectomy with extrahepatic bile duct resection is associated with a higher risk of postoperative regurgitation cholangitis and a lower regeneration rate of a remnant liver after resection [11,12]. Portal vein embolization to a resected liver increases its applicability due to the advancement of interventional radiology. Endoscopic nasobiliary drainage is a more suitable method of biliary drainage than endoscopic biliary stenting or percutaneous transhepatic biliary drainage because endoscopic nasobiliary drainage is less associated with preoperative cholangitis, which leads to posthepatectomy liver failure and peritoneal/pleural seeding metastasis [7,13–15]. In addition, perioperative administration of synbiotics and bile replacement maintain the intestinal mucosal integrity [16,17], and a perioperative exercise program, i.e., prehabilitation and rehabilitation, strengthens the performance status of a patient and increases the tolerance against fatal postoperative complications [18]. Therefore, meticulous perioperative management is an important key to successful hilar cholangiocarcinoma surgeries.
3.2. Hepatopancreaticoduodenectomy for tumors with extensive longitudinal tumor spreading The standard surgical procedure for hilar cholangiocarcinoma involves cutting the distal bile duct at the cranial side of the pancreas head, and a negative surgical margin is achieved in the majority of cases. However, in the other cases, tumors exhibit extensive ductal spreading, invading longitudinally from the hepatic hilus to the lower bile duct. In these cases, a negative surgical margin cannot be achieved unless an extended procedure resecting the whole extrahepatic biliary system is conducted. Hepatopancreaticoduodenectomy (HPD), which involves the resection of the whole extrahepatic biliary system with the adjacent liver and pancreatoduodenum, is the only procedure that involves resecting the entire extrahepatic biliary system (Fig. 1c). HPD was initially introduced to treat advanced gallbladder cancer and then suggested as a treatment for cholangiocarcinomas with extensive longitudinal tumor spreading [31,32]. Although the applicability of HPD had been doubted for decades due to its unsatisfactory surgical/survival outcomes, most recent reports have indicated improved surgical outcomes with a mortality of 0–3% and favorable survival outcomes [33,34]. However, HPD remains associated with a high probability of postoperative complications. Posthepatectomy liver failure and postoperative pancreatic fistula are serious but not uncommon complications after HPD. The aggressive use of portal vein embolization decreases the incidence of posthepatectomy liver failure [33], and twostage pancreaticojejunostomy may decrease the incidence of a grade C postoperative pancreatic fistula; however, this strategy does not decrease the incidence of a grade B postoperative pancreatic fistula and inherently requires a second-stage reconstruction surgery [34–36].
3. Extended surgical procedures for advanced hilar cholangiocarcinoma 3.1. Trisectionectomy for bismuth type IV tumors The extent of intrahepatic biliary invasion is a crucial factor that determines surgical indication and the type of hepatectomy. The Bismuth classification system [19] has been widely used because this classification system not only aids discussions regarding surgical decision-making and resectability but also partially indicates the aggressiveness of a tumor. In this classification system, a hilar cholangiocarcinoma with bilateral involvement of second-order biliary radicles is defined as a Bismuth type IV tumor. Data from a leading US hepatobiliary center in the early 2000s indicated that Bismuth type IV tumors have previously been associated with poor overall survival [20], and thus, this type of tumor was defined as a T4 disease in the 7th edition of the international cancer staging manual and regarded as an unresectable tumor [21]. Hepatic trisectionectomy, which involves proximally cutting the hepatic bile ducts beyond the confluence of the second biliary radicles, has been suggested for the treatment of Bismuth type IV tumors. Trisectionectomy is oncologically more advantageous than hemi-hepatectomy for the treatment of Bismuth type IV tumors because a longer length of a resected proximal bile duct and an increased chance of a tumor-free ductal margin can be achieved [22,23]. An aggressive indication for trisectionectomy provides patients with Bismuth type IV 3
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Although it remains not widely accepted worldwide, HPD theoretically increases the number of resectable hilar cholangiocarcinomas. Recent results have suggested that this procedure is currently regarded as an extended but standard option for the treatment of hilar cholangiocarcinoma with extensive longitudinal tumor spreading. Further improvements in perioperative management and surgical techniques are required to increase the benefits of this procedure.
4.2. Neoadjuvant therapy for initially unresectable hilar cholangiocarcinoma Another multidisciplinary approach for the treatment of advanced hilar cholangiocarcinoma is conversion therapy for the treatment of initially unresectable tumors. Several nonsurgical therapies are recommended for the treatment of locally advanced unresectable hilar cholangiocarcinoma as first-line therapies that provide prolonged overall survival and a substantial response [1,50]. A minority of patients have shown an optimal response that converted initially unresectable tumors into resectable tumors. The resection of initially unresectable tumors after confirming a substantial response to chemotherapy or chemoradiotherapy has been validated for other types of tumors, such as initially unresectable colorectal liver metastases [51], locally advanced borderline-resectable pancreatic adenocarcinoma [52], and intrahepatic cholangiocarcinoma [53]. Although there are limited numbers of retrospective case studies [54] and the survival benefit of this strategy needs to be validated in a prospective or retrospective cohort study with a large number of patients, a more powerful regimen possibly increases the number of candidates who benefit from this strategy.
3.3. Combined vascular resection with reconstruction for tumors that involve hepatic vascular structures Advanced hilar cholangiocarcinoma is likely to involve adjacent vascular structures for hepatic inflow due to the anatomical vicinity between the hilar bile duct and the portal vein or hepatic artery. The international cancer staging system defines T4 tumors as the following: those involving the main portal vein or its bilateral branch, those involving the common hepatic artery, or those involving unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement [25]. Combined vascular resection with reconstruction has been attempted to achieve R0 resection in patients with T4 hilar cholangiocarcinoma. From a technical perspective, this combined procedure consists of the following three different modes of vascular resection(s) with reconstruction: the portal vein alone (PVR), hepatic artery alone (HAR), and hepatic artery and portal vein (HAPVR) (Fig. 1d). The PVR is the most common combined vascular resection/ reconstruction procedure and is considered a standard option for the treatment of advanced hilar cholangiocarcinoma [37–39]. In contrast, the efficacies of other combined vascular resection procedures remain under debate. Our institution has reported on 50 consecutive patients who underwent HAPVR with acceptable surgical and survival outcomes [40], while high morbidity and mortality with shorter survival outcomes have been reported in some retrospective studies with a few patients who underwent HAR or HAPVR [41,42]. A precise understanding of the hilar vascular anatomy [43] and a detailed preoperative assessment of the extent of vascular involvement [44,45] is necessary for a successful surgery with a negative surgical margin.
Summary In summary, extended resection procedures, which are aggressive surgical approaches, are safely performed under meticulous preoperative management. Three extended resection procedures, including hepatic trisectionectomy, HPD, and combined vascular resection with reconstruction, expand the surgical indication for hilar cholangiocarcinoma and are regarded as a standard option for the treatment of advanced hilar cholangiocarcinoma. In addition, the combination of a more powerful chemotherapeutic regimen and an aggressive surgical approach could accelerate the multidisciplinary approach for the treatment of initially unresectable hilar cholangiocarcinoma. Conflicts of interest The authors have no conflicts of interest to declare.
4. A multidisciplinary approach for the treatment of advanced hilar cholangiocarcinoma
Appendix A. Supplementary data
4.1. Adjuvant therapy for the treatment of advanced hilar cholangiocarcinoma after resection
Supplementary data to this article can be found online at https:// doi.org/10.1016/j.suronc.2019.07.002.
A high probability of recurrence, even after a curative-intent surgical resection, is a serious issue in advanced hilar cholangiocarcinoma. The high recurrence rate after resection has motivated the development of a multidisciplinary approach that involves the combined use of surgical resection and a perioperative nonsurgical treatment. A metaanalysis of mostly retrospective data has suggested a potential benefit of adjuvant chemotherapy in patients with lymph node metastasis and/ or microscopic residual tumors, and the international guidelines have recommended the administration of adjuvant chemotherapy in patients with these risk factors [46]. Recently published randomized phase 3 studies, which were expected to demonstrate the efficacy of adjuvant therapy for biliary malignancies, yielded inconsistent results. The phase 3 BILCAP study showed improved overall survival after treatment with the adjuvant capecitabine in the per-protocol analysis, but the overall survival did not achieve statistical significance in the intent-to-treat analysis [47]. In contrast, two other phase 3 studies, which include the PRODIGE 12 study that compared GEMOX adjuvant therapy with surgery alone and the BCAT study that compared gemcitabine adjuvant monotherapy with surgery alone, did not show a survival benefit due to adjuvant chemotherapy [48,49]. Further prospective studies and/or integration analyses are needed to demonstrate the efficacy of adjuvant therapy for the treatment of advanced hilar cholangiocarcinoma.
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Contents lists available at ScienceDirect
Surgical Oncology journal homepage: www.elsevier.com/locate/suronc
Advanced hilar cholangiocarcinoma: An aggressive surgical approach for the treatment of advanced hilar cholangiocarcinoma: Perioperative management, extended procedures, and multidisciplinary approaches Takashi Mizuno∗, Tomoki Ebata, Masato Nagino Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
ARTICLE INFO
ABSTRACT
Keywords: Perihilar cholangiocarcinoma Vascular reconstruction Hepatopancreaticoduodenectomy
Hilar cholangiocarcinoma is a highly intractable malignancy. One of the reasons for its intractability is that most patients with the disease are diagnosed with an advanced stage of the disease at their initial presentation. Surgical resection is the standard therapy for hilar cholangiocarcinoma, providing a chance for a cure, and an aggressive surgical approach substantially increases the number of resectable tumors that are initially regarded as unresectable tumors. The success and standardization of the aggressive approach is warranted by meticulous preoperative management that prevents fatal postoperative complications. Extended resection procedures, including hepatic trisectionectomy for Bismuth type IV tumors, hepatopancreaticoduodenectomy for tumors with extensive longitudinal tumor spreading, and combined vascular resection with reconstruction for tumors with the involvement of hepatic vascular structures, have been challenged to expand the surgical indication. Due to acceptable surgical/survival outcomes, the three extended procedures are currently regarded as extended but standard options in specialized hepatobiliary centers. Although it remains a controversial multidisciplinary approach, the combination of these extended procedures with an adjuvant/neoadjuvant treatment is a promising approach for further improving the resectability of tumors and the survival of patients.
1. Introduction Hilar cholangiocarcinoma is a highly intractable malignancy. One of the reasons for the intractability is that most patients with the disease are diagnosed with advanced disease at their initial presentation. Advancements in nonsurgical treatments have prolonged the overall survival in patients with metastatic/locally unresectable tumors [1]; however, surgical resection undoubtedly remains the standard therapy for hilar cholangiocarcinoma, providing a chance for a cure. Refinements in surgical techniques and perioperative management over the past two decades have not only improved surgical/survival outcomes after resection but also expanded the indication for surgery. In addition, several extended resection procedures have also been attempted to treat advanced hilar cholangiocarcinoma, which was previously regarded as unresectable [2]. Furthermore, these extended procedures have been combined with adjuvant/neoadjuvant treatments for further improved overall survival, although this strategy remains controversial.
In this review article, the following three topics associated with aggressive surgical approaches were discussed: perioperative management, extended surgical procedures, and multidisciplinary approaches. Perioperative management was addressed first because meticulous perioperative management is crucial for the success of aggressive surgical approaches. Second, the three following extended resection procedures for various types of advanced hilar cholangiocarcinoma were discussed: hepatic trisectionectomy for Bismuth type IV tumors, hepatectomy with pancreaticoduodenectomy (HPD) for tumors with extensive longitudinal spreading and combined vascular resection with reconstruction for tumors involving adjacent vascular structures. Finally, multidisciplinary treatment strategies, including adjuvant therapy for resectable tumors and conversion therapy for initially unresectable tumors, were discussed because of increasing evidence in this field.
Abbreviations: HPD, hepatectomy with pancreaticoduodenectomy; PVR, combined resection with reconstruction of the portal vein; HAR, combined resection with reconstruction of the hepatic artery; HAPVR, combined simultaneous resection of the hepatic artery and portal vein ∗ Corresponding author. Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail address: [email protected] (T. Mizuno). https://doi.org/10.1016/j.suronc.2019.07.002 Received 27 May 2019; Received in revised form 27 June 2019; Accepted 7 July 2019 0960-7404/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Takashi Mizuno, Tomoki Ebata and Masato Nagino, Surgical Oncology, https://doi.org/10.1016/j.suronc.2019.07.002
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Fig. 1. Schematics and images of a) hepatic right trisectionectomy, b) hepatic left trisectionectomy, c) right hepatectomy with pancreaticoduodenectomy, and d) left trisectionectomy combined with simultaneous resection of the hepatic artery and portal vein. B2+3, left lateral sectoral bile duct; HA, hepatic artery; PV, portal vein; IVC, inferior vena cava; RHV, right hepatic vein; RPHD, right posterior hepatic duct; LHD, left hepatic duct; MHV, middle hepatic vein.
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2. Meticulous perioperative management for extended resection procedures
tumors with an increased chance of R0 resection and prolonged overall survival, and data from a Japanese multicenter retrospective study has indicated that the prognostic ability of the 7th edition staging system can be enhanced if the presence of Bismuth type IV tumors are removed from the T4 determinants [24]. In the newest 8th edition of the American Joint Committee on Cancer (AJCC) cancer staging manual, Bismuth type IV have been removed from the T4 category [25]. The revision suggests that these Bismuth type IV tumors are no longer contraindications for resection. Right trisectionectomy is less technically difficult than left trisectionectomy because of the presence of clear anatomical landmarks and a smaller hepatic transection surface [26]. Notably, anatomically extended right hepatic trisectionectomy should be performed to achieve a greater chance of a tumor-free ductal margin (Fig. 1a). The procedure is a completely different procedure from a classic right hepatic trisectionectomy because the proximal bile duct is cut at the left side of the umbilical portion of the portal vein [27]. Although right trisectionectomy is advantageous from the perspective of local tumor eradication, the smallest volume of a liver remnant risks posthepatectomy liver failure. Compared with right portal vein embolization alone, right portal vein embolization with segment 4 embolization is recommended to avoid posthepatectomy liver failure because it provides an increased rate of hypertrophy of a future liver remnant [28]. Recently, the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure has been enthusiastically introduced to more rapidly increase the volume of future liver remnants; however, this procedure for the treatment of hilar cholangiocarcinoma is discouraging due to extremely high mortality [29]. In contrast, left trisectionectomy is a much more technically demanding procedure because of an extensively wide hepatic transection surface and a lack of anatomical landmarks (Fig. 1b). [30] In addition, the right hepatic artery is more likely to be involved due to the anatomical vicinity between the artery and hilar bile ducts. Thus, resection with reconstruction of the right hepatic artery is likely to be combined with left trisectionectomy, which is discussed in a subsequent section.
Before discussing the aggressive surgical approach, details regarding perioperative management must be addressed because surgical outcomes depend on the quality of perioperative management in addition to surgical techniques. Nevertheless, the reported surgical outcomes after hilar cholangiocarcinoma surgery are inconsistent between tertiary hepatobiliary centers, with postoperative mortality ranging from 0 to 13% [2–4]. It is assumed that this inconsistency is partially attributed to differences in perioperative management between the centers. The most serious postoperative complication that is the main cause of 90-day mortality is posthepatectomy liver failure. To avoid fatal complications, patients should be treated with the following meticulous perioperative management strategies: precise evaluation of the functional capacity of the future liver remnant [5], aggressive use of preoperative portal vein embolization [6], and appropriate biliary drainage using endoscopic nasobiliary drainage [7]. Several analytical methods are available for the estimation of the functional capacity of future liver remnant [8–10]. Notably, background cholestatic liver is associated with decreased hepatic function even after biliary decompression, and major hepatectomy with extrahepatic bile duct resection is associated with a higher risk of postoperative regurgitation cholangitis and a lower regeneration rate of a remnant liver after resection [11,12]. Portal vein embolization to a resected liver increases its applicability due to the advancement of interventional radiology. Endoscopic nasobiliary drainage is a more suitable method of biliary drainage than endoscopic biliary stenting or percutaneous transhepatic biliary drainage because endoscopic nasobiliary drainage is less associated with preoperative cholangitis, which leads to posthepatectomy liver failure and peritoneal/pleural seeding metastasis [7,13–15]. In addition, perioperative administration of synbiotics and bile replacement maintain the intestinal mucosal integrity [16,17], and a perioperative exercise program, i.e., prehabilitation and rehabilitation, strengthens the performance status of a patient and increases the tolerance against fatal postoperative complications [18]. Therefore, meticulous perioperative management is an important key to successful hilar cholangiocarcinoma surgeries.
3.2. Hepatopancreaticoduodenectomy for tumors with extensive longitudinal tumor spreading The standard surgical procedure for hilar cholangiocarcinoma involves cutting the distal bile duct at the cranial side of the pancreas head, and a negative surgical margin is achieved in the majority of cases. However, in the other cases, tumors exhibit extensive ductal spreading, invading longitudinally from the hepatic hilus to the lower bile duct. In these cases, a negative surgical margin cannot be achieved unless an extended procedure resecting the whole extrahepatic biliary system is conducted. Hepatopancreaticoduodenectomy (HPD), which involves the resection of the whole extrahepatic biliary system with the adjacent liver and pancreatoduodenum, is the only procedure that involves resecting the entire extrahepatic biliary system (Fig. 1c). HPD was initially introduced to treat advanced gallbladder cancer and then suggested as a treatment for cholangiocarcinomas with extensive longitudinal tumor spreading [31,32]. Although the applicability of HPD had been doubted for decades due to its unsatisfactory surgical/survival outcomes, most recent reports have indicated improved surgical outcomes with a mortality of 0–3% and favorable survival outcomes [33,34]. However, HPD remains associated with a high probability of postoperative complications. Posthepatectomy liver failure and postoperative pancreatic fistula are serious but not uncommon complications after HPD. The aggressive use of portal vein embolization decreases the incidence of posthepatectomy liver failure [33], and twostage pancreaticojejunostomy may decrease the incidence of a grade C postoperative pancreatic fistula; however, this strategy does not decrease the incidence of a grade B postoperative pancreatic fistula and inherently requires a second-stage reconstruction surgery [34–36].
3. Extended surgical procedures for advanced hilar cholangiocarcinoma 3.1. Trisectionectomy for bismuth type IV tumors The extent of intrahepatic biliary invasion is a crucial factor that determines surgical indication and the type of hepatectomy. The Bismuth classification system [19] has been widely used because this classification system not only aids discussions regarding surgical decision-making and resectability but also partially indicates the aggressiveness of a tumor. In this classification system, a hilar cholangiocarcinoma with bilateral involvement of second-order biliary radicles is defined as a Bismuth type IV tumor. Data from a leading US hepatobiliary center in the early 2000s indicated that Bismuth type IV tumors have previously been associated with poor overall survival [20], and thus, this type of tumor was defined as a T4 disease in the 7th edition of the international cancer staging manual and regarded as an unresectable tumor [21]. Hepatic trisectionectomy, which involves proximally cutting the hepatic bile ducts beyond the confluence of the second biliary radicles, has been suggested for the treatment of Bismuth type IV tumors. Trisectionectomy is oncologically more advantageous than hemi-hepatectomy for the treatment of Bismuth type IV tumors because a longer length of a resected proximal bile duct and an increased chance of a tumor-free ductal margin can be achieved [22,23]. An aggressive indication for trisectionectomy provides patients with Bismuth type IV 3
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Although it remains not widely accepted worldwide, HPD theoretically increases the number of resectable hilar cholangiocarcinomas. Recent results have suggested that this procedure is currently regarded as an extended but standard option for the treatment of hilar cholangiocarcinoma with extensive longitudinal tumor spreading. Further improvements in perioperative management and surgical techniques are required to increase the benefits of this procedure.
4.2. Neoadjuvant therapy for initially unresectable hilar cholangiocarcinoma Another multidisciplinary approach for the treatment of advanced hilar cholangiocarcinoma is conversion therapy for the treatment of initially unresectable tumors. Several nonsurgical therapies are recommended for the treatment of locally advanced unresectable hilar cholangiocarcinoma as first-line therapies that provide prolonged overall survival and a substantial response [1,50]. A minority of patients have shown an optimal response that converted initially unresectable tumors into resectable tumors. The resection of initially unresectable tumors after confirming a substantial response to chemotherapy or chemoradiotherapy has been validated for other types of tumors, such as initially unresectable colorectal liver metastases [51], locally advanced borderline-resectable pancreatic adenocarcinoma [52], and intrahepatic cholangiocarcinoma [53]. Although there are limited numbers of retrospective case studies [54] and the survival benefit of this strategy needs to be validated in a prospective or retrospective cohort study with a large number of patients, a more powerful regimen possibly increases the number of candidates who benefit from this strategy.
3.3. Combined vascular resection with reconstruction for tumors that involve hepatic vascular structures Advanced hilar cholangiocarcinoma is likely to involve adjacent vascular structures for hepatic inflow due to the anatomical vicinity between the hilar bile duct and the portal vein or hepatic artery. The international cancer staging system defines T4 tumors as the following: those involving the main portal vein or its bilateral branch, those involving the common hepatic artery, or those involving unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement [25]. Combined vascular resection with reconstruction has been attempted to achieve R0 resection in patients with T4 hilar cholangiocarcinoma. From a technical perspective, this combined procedure consists of the following three different modes of vascular resection(s) with reconstruction: the portal vein alone (PVR), hepatic artery alone (HAR), and hepatic artery and portal vein (HAPVR) (Fig. 1d). The PVR is the most common combined vascular resection/ reconstruction procedure and is considered a standard option for the treatment of advanced hilar cholangiocarcinoma [37–39]. In contrast, the efficacies of other combined vascular resection procedures remain under debate. Our institution has reported on 50 consecutive patients who underwent HAPVR with acceptable surgical and survival outcomes [40], while high morbidity and mortality with shorter survival outcomes have been reported in some retrospective studies with a few patients who underwent HAR or HAPVR [41,42]. A precise understanding of the hilar vascular anatomy [43] and a detailed preoperative assessment of the extent of vascular involvement [44,45] is necessary for a successful surgery with a negative surgical margin.
Summary In summary, extended resection procedures, which are aggressive surgical approaches, are safely performed under meticulous preoperative management. Three extended resection procedures, including hepatic trisectionectomy, HPD, and combined vascular resection with reconstruction, expand the surgical indication for hilar cholangiocarcinoma and are regarded as a standard option for the treatment of advanced hilar cholangiocarcinoma. In addition, the combination of a more powerful chemotherapeutic regimen and an aggressive surgical approach could accelerate the multidisciplinary approach for the treatment of initially unresectable hilar cholangiocarcinoma. Conflicts of interest The authors have no conflicts of interest to declare.
4. A multidisciplinary approach for the treatment of advanced hilar cholangiocarcinoma
Appendix A. Supplementary data
4.1. Adjuvant therapy for the treatment of advanced hilar cholangiocarcinoma after resection
Supplementary data to this article can be found online at https:// doi.org/10.1016/j.suronc.2019.07.002.
A high probability of recurrence, even after a curative-intent surgical resection, is a serious issue in advanced hilar cholangiocarcinoma. The high recurrence rate after resection has motivated the development of a multidisciplinary approach that involves the combined use of surgical resection and a perioperative nonsurgical treatment. A metaanalysis of mostly retrospective data has suggested a potential benefit of adjuvant chemotherapy in patients with lymph node metastasis and/ or microscopic residual tumors, and the international guidelines have recommended the administration of adjuvant chemotherapy in patients with these risk factors [46]. Recently published randomized phase 3 studies, which were expected to demonstrate the efficacy of adjuvant therapy for biliary malignancies, yielded inconsistent results. The phase 3 BILCAP study showed improved overall survival after treatment with the adjuvant capecitabine in the per-protocol analysis, but the overall survival did not achieve statistical significance in the intent-to-treat analysis [47]. In contrast, two other phase 3 studies, which include the PRODIGE 12 study that compared GEMOX adjuvant therapy with surgery alone and the BCAT study that compared gemcitabine adjuvant monotherapy with surgery alone, did not show a survival benefit due to adjuvant chemotherapy [48,49]. Further prospective studies and/or integration analyses are needed to demonstrate the efficacy of adjuvant therapy for the treatment of advanced hilar cholangiocarcinoma.
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