Chemoradiotherapy for Initially Unresectable Locally Advanced Cholangiocarcinoma

World Journal of Surgery, Mar 2018

Tatsuaki Sumiyoshi, Yasuo Shima, Takehiro Okabayashi, Yuji Negoro, Yasuhiro Shimada, Jun Iwata, Manabu Matsumoto, Yasuhiro Hata, Yoshihiro Noda, Kenta Sui, et al.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2Fs00268-018-4558-1.pdf

Chemoradiotherapy for Initially Unresectable Locally Advanced Cholangiocarcinoma

Chemoradiotherapy for Initially Unresectable Locally Advanced Cholangiocarcinoma Tatsuaki Sumiyoshi 0 1 2 3 4 Yasuo Shima 0 1 2 3 4 Takehiro Okabayashi 0 1 2 3 4 Yuji Negoro 0 1 2 3 4 Yasuhiro Shimada 0 1 2 3 4 Jun Iwata 0 1 2 3 4 Manabu Matsumoto 0 1 2 3 4 Yasuhiro Hata 0 1 2 3 4 Yoshihiro Noda 0 1 2 3 4 Kenta Sui 0 1 2 3 4 Taijiro Sueda 0 1 2 3 4 0 Department of Medical Oncology, Kochi Health Sciences Center , Kochi , Japan 1 Departments of Gastroenterological Surgery, Kochi Health Sciences Center , 2125 Ike, Kochi , Japan 2 & Tatsuaki Sumiyoshi 3 Department of Surgery, Applied Life Sciences Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima , Japan 4 Departments of Diagnostic Pathology, Kochi Health Sciences Center , Kochi , Japan Objective Surgical resection is the only available treatment for achieving long-term survival in cholangiocarcinoma. The purpose of this study is to elucidate the utility of chemoradiotherapy for initially unresectable locally advanced cholangiocarcinoma. Methods Unresectable locally advanced cholangiocarcinoma was defined as those in which radical surgery could not be achieved even with aggressive surgical procedure. Fifteen candidates (7 intrahepatic cholangiocarcinomas and 8 hilar cholangiocarcinomas) underwent chemoradiotherapy. Fourteen of the 15 patients received oral S-1 chemotherapy. Radiotherapy was administered with 50 Gy for each patient. After chemoradiotherapy, the resectability of each cholangiocarcinoma was reexamined. Results Of the 15 patients with initially unresectable locally advanced cholangiocarcinoma, 11 (73.3%) were judged to have resectable cholangiocarcinoma after chemoradiotherapy, and received radical hepatectomy (R0 resection in 9 patients). Among the 11 patients who underwent surgical resection, 4 had recurrence-free survival and the median survival time (MST) was 37 months. The overall 1-, 2-, and 5-year survival rates were 80.8, 70.7 and 23.6%, respectively. Among the 4 patients who were unable to receive surgery, 3 died of the primary disease and the MST was 10 months. The overall 1- and 2-year survival rates were 37.5 and 0%, respectively. Patients who received radical surgery had significantly longer survival time than those who were unable to receive surgery (p = 0.027). Conclusions Chemoradiotherapy allowed patients with initially unresectable locally advanced cholangiocarcinomas to be reclassified as surgical candidates in a substantial proportion. Chemoradiotherapy might be one of the treatment options for similarly advanced cholangiocarcinomas. - Departments of Radiology, Kochi Health Sciences Center, Kochi, Japan Introduction Cholangiocarcinoma accounts for approximately 3% of all gastrointestinal malignancies [ 1, 2 ], and its incidence is increasing [ 3, 4 ]. Early diagnosis of cholangiocarcinoma is difficult because of the absence of effective screening [ 5, 6 ], and the majority of patients who present with this disease have tumors that are unresectable because of local tumor extension or distant metastasis [ 7, 8 ]. The prognosis of unresectable cholangiocarcinoma is extremely poor, although a recent large-scale phase III clinical trial of gemcitabine and cisplatin chemotherapy (ABC-02) showed an improved median survival time of 11.7 months [ 9 ]. Surgical resection is the only available treatment for achieving long-term survival in patients with cholangiocarcinoma. However, much as 50% of patients who undergo exploration with curative intent are found to have locally aggressive, unresectable tumors, despite the absence of distant metastasis at the initial presentation [ 5 ]. To reclassify patients with unresectable locally advanced cholangiocarcinomas as surgical candidates, chemoradiotherapy (CRT) has been administered at this institution. The superiority of CRT to chemotherapy is unclear for cholangiocarcinoma. However, McMaster and Nelson reported the high response rate of CRT and subsequent high R0 resection rate for advanced cholangiocarcinoma [ 10, 11 ]. Further, a Korean National Cancer Center group reported that CRT was associated with longer progressionfree survival and overall survival than chemotherapy alone in patients with unresectable advanced intrahepatic cholangiocarcinoma [12]. Considering these results, we have applied CRT for patients with unresectable locally advanced cholangiocarcinoma. Here, we have investigated the clinical utility of this CRT. Methods Patients The clinical database of Kochi Health Science Center was reviewed retrospectively to identify patients who underwent CRT for unresectable locally advanced cholangiocarcinoma between January 2006 and August 2016. The initial diagnosis of cholangiocarcinoma was made based on multiple detector computed tomography (MDCT), cholangiography, and cytology. Five-phase computed tomography (CT) images (1 unenhanced image and 4 contrast-enhanced images) were routinely obtained and the scanning parameters for each phase were as follows: 1-mm collimation, 3-mm slice thickness, and 3-mm reconstruction interval. Patients with distant metastases were excluded. Initially, unresectable locally advanced cholangiocarcinoma was defined as those in which radical surgery could not be achieved, even with aggressive surgical procedure (Figs. 1, 2). The specific inclusion criteria were as follows: (1) cancer invasion to bilateral hepatic arteries that prevented reconstruction, (2) cancer invasion to bilateral portal veins that prevented reconstruction, (3) cancer invasion to 3 hepatic veins that prevented reconstruction, (4) broad infiltration to bilateral bile ducts that prevented the achievement of curative resection, (5) broad extrahepatic perineural invasion extending around the proper hepatic artery and common hepatic artery. As a relative indication, (6) cancer invasion to both 2 hepatic veins and the inferior vena cava (IVC) was also included. The ethics committees of Kochi Health Sciences Center approved the study. CRT regimen Of the 15 patients who underwent CRT, 14 received S-1 chemotherapy. The remaining 1 patient received CDDP & CPT-11 chemotherapy. S-1 is an orally administered drug, comprising the 5-FU prodrug tegafur and two molecules, gimeracil and oteracil potassium, that increase the blood concentration, and enhance the anti-tumor effect of 5-FU [ 13, 14 ]. S-1 was administered orally twice daily at a dose calculated according to the body-surface area (\1.25 m2, 60 mg/day; ]1.25 to \1.5 m2, 80 mg/day; ]1.5 m2, 100 mg/day) on days 1 through 14 of a 21-day cycle. Intensity-modulated radiotherapy was administered with a total dose of 50 Gy delivered in 25 fractions over 5 weeks. The gross tumor volume (GTV) was defined as the area of solid macroscopic tumors that was enhanced on MDCT imaging. In patients with broad extra-hepatic perineural invasion, the area around proper hepatic artery and common hepatic artery were also included in the GTV. Assessment Physical examinations, complete blood cell counts, and biochemistry tests were routinely conducted every week. Objective tumor response was evaluated every 4–6 weeks by MDCT. For patients with intrahepatic cholangiocarcinoma (ICC), the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) were applied. In patients with hilar cholangiocarcinoma (HC), halation from the biliary drainage tube usually makes it difficult to obtain an accurate evaluation of tumor size. Therefore, the degree of vascular invasion was assessed in cases with a biliary drainage tube, and the main tumor size was assessed in cases without this tube. An established team of medical experts, including 5 hepatobiliary pancreatic surgeons, 5 radiologists, and 1 oncologist, evaluated response to CRT, Pre-CRT Case 9 (a) Pre-CRT Case 3 (c) Pre-CRT Case 4 (e) Fig. 1 Unresectable locally advanced cholangiocarcinoma and its response to chemoradiotherapy (CRT). Cases with severe invasion to the hepatic artery, portal vein, or hepatic vein are shown. a Case 9 (invasion to bilateral hepatic arteries). The hilar cholangiocarcinoma originated from the left hepatic duct, and it invaded both the bilateral hepatic arteries and bilateral portal veins. The cancer at the common hepatic duct (black arrow) involved the right hepatic artery (dotted arrow). b After CRT, the cancer invasion around the right hepatic artery was obviously diminished (dotted arrow). The arrow shows the biliary drainage tube. R0 resection was achieved by left hemihepatectomy. c Case 3 (invasion to bilateral portal veins). The intrahepatic cholangiocarcinoma had extensively invaded the hepatic hilus and whether the advanced cancer could be reclassified as resectable in each case. Patients with broad extra-hepatic perineural invasion became candidates for surgery if there was no remarkable progression of the perineural invasion on MDCT. The surgically resected specimens were assessed by 2 expert pathologists. Surgical outcome, recurrence, and overall survival were assessed. Post-CRT Case 9 Post-CRT Case 3 Post-CRT Case 4 (arrow). The umbilical portion was also involved (dotted arrow). d After CRT, the cancer invasion around the hepatic hilus diminished (arrow), and reconstruction was considered to be feasible for the left portal vein (dotted arrow). R0 resection was achieved by right hemihepatectomy with left portal vein reconstruction. e Case 4 (invasion to 3 hepatic veins). The intrahepatic cholangiocarcinoma invaded the right hepatic vein (dotted arrow). f After CRT, the bulky cholangiocarcinoma shrank and the invasion around the right hepatic vein was also diminished (dotted arrow). Reconstruction was considered to be feasible for the right hepatic vein. R0 resection was achieved by left trisegmentectomy with right hepatic vein reconstruction Statistical analysis Patients alive in January 2017 were censored at the time of follow-up. Survival curves were established using the Kaplan–Meier method, and a log-rank test was applied to determine the statistical significance of differences in survival. A P value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed using SPSS Statistics 19 (IBM, Armonk, NY, USA). Pre-CRT Case 8 (a) Pre-CRT Case 2 (c) Pre-CRT Case 1 (e) RHV MHV Post-CRT Case 8 Post-CRT Case 2 Post-CRT Case 1 MHV RHV Fig. 2 Unresectable locally advanced cholangiocarcinoma and its response to chemoradiotherapy (CRT). Cases with severe invasion to the bile duct, extrahepatic neuroplexus, or hepatic vein and inferior vena cava are shown. a Case 8 (broad infiltration to bilateral bile duct). The hilar cholangiocarcinoma extensively invaded the bilateral secondary bile duct branches (black arrow). b After CRT, the hilar cholangiocarcinoma shrank (black arrow). R0 resection could be achieved by left hemihepatectomy. c Case 2 (broad extra-hepatic perineural invasion). The intrahepatic cholangiocarcinoma originated from the left intrahepatic bile duct and extensively invaded the neuroplexus around the proper hepatic artery (dotted arrow) and common hepatic artery. d After CRT, the low-density area around the proper hepatic artery did not shrink (dotted arrow). At laparotomy, analysis of an intraoperative frozen section revealed no residual cancer around the proper hepatic artery or common hepatic artery, although residual severe perineural invasion was confirmed in the hepatic hilus. R0 resection was achieved by left hemihepatectomy. e Case 1 (invasion to both 2 hepatic veins and the inferior vena cava). The middle hepatic vein (MHV), right hepatic vein (RHV), and inferior vena cava were involved by the intrahepatic cholangiocarcinoma (black arrow). f After CRT, the cholangiocarcinoma shrank (arrow), and caudate lobectomy with S4 segmentectomy and MHV resection were performed. The patient showed no local recurrence, despite microscopic cancer exposure on the cut surface (R1 resection) Results Clinical characteristics Fifteen patients were diagnosed with initially unresectable local advanced tumors according to the inclusion criteria (Table 1). The patient cohort consisted of 9 men and 6 women, with a median age of 73 years (range 54–85 years). The median follow-up of all patients and of the patients who received radical surgery after CRT was 18 months (range 6–105) and 32 months (range 6–105), respectively. The final diagnosis was ICC in 7 patients and HC in 8 patients. One of the 7 patients with ICC and 5 of the 8 patients with HC showed obstructive jaundice and received biliary drainage. CRT was initiated after serum total bilirubin levels had decreased to \2.0 mg/dL. The 7 ICCs were unresectable for the following reasons: broad extra-hepatic perineural invasion in 4 patients, invasion to bilateral portal veins in 1 patient, invasion to 2 hepatic veins and IVC in 1 patient, and invasion to 3 hepatic veins in 1 patient. The 8 HCs were unresectable for the following reasons: broad extra-hepatic perineural invasion in 3 patients, and broad bile duct infiltration in 3 patients. Two HC patients had cholangiocarcinoma that was unresectable for 2 reasons: invasion to bilateral portal veins and bilateral hepatic arteries. Four patients (1 with ICC and 3 with HC) underwent portal vein embolization because of the insufficient remnant liver function after CRT. Response to CRT Tumor diameter, response evaluation, and resectability after CRT are summarized in Table 1. Of the 7 patients with ICC, 6 (85.7%) showed tumor shrinkage. According to the RECIST criteria, 4 (57.1%) patients had partial response (PR), 1 (14.3%) had stable disease (SD), and 2 (28.6%) had progressive disease (PD). Of 8 HC patients, 3 (37.5%) were observed to have tumor shrinkage, and 1 (12.5%) were observed to have tumor progression. Finally, 11 of the 15 patients were judged to have resectable cholangiocarcinoma after CRT, and received radical hepatectomy, including 5 patients with ICC and 6 with HC (Figs. 1, 2). Four (26.7%) patients were judged to have unresectable cholangiocarcinoma for the following reasons: distant metastasis in 2 ICC patients, primary tumor progression in 1 HC patient, and deteriorated performance status in 1 HC patient. Surgery Surgical outcomes and adjuvant chemotherapy regimens are summarized in Table 2. Except for 1 ICC patient who received segmentectomy, the surgical procedures were mainly lobectomy or trisegmentectomy. Concomitant extrahepatic bile duct resection and regional lymph node dissection were performed in 9 (81.8%) and 11 (100%) patients, although irradiation made hepatoduodenal ligament dissection harder. Revascularization was performed in 3 patients (portal vein reconstruction in 1 ICC patient and 1 HC patient, and right hepatic vein reconstruction in 1 ICC patient). The median surgical time was 338 min, and the range was 251–518 min. The median blood loss was 700 g, and the range was 120–1866 g. Surgery-related severe complication occurred in 3 (27.3%) patients, including 1 ICC patient with liver failure, 1 ICC patient with pleural effusion, and 1 HC patient with intra-abdominal hemorrhage. As an RT-related complication, severe gastritis occurred in 1 ICC patient. However, the 90-day postoperative mortality was zero. R0 and R1 resection were achieved in 9 and 2 patients, respectively. There was no case of R2 resection. Four of 7 patients with broad extra-hepatic perineural invasion received radical surgery, and pathological examination revealed residual perineural invasion in the hepatic hilum in all resected cases. However, intraoperative frozen sections revealed no residual cancer around the proper hepatic artery or common hepatic artery, and R0 resections were achieved in all 4 of these cases. As chronic complication, 1 HC patient showed stenosis of bilioenteric anastomosis, and required percutaneous transhepatic biliary drainage 8 months after the surgery. Remaining 10 patients showed no sign of cholangitis. Vascular complication occurred in 1 ICC patient (case 4), and endovascular thrombectomy for occluded right hepatic vein was performed. Prognosis In 5 ICC patients, 3 showed tumor recurrence, and the site was lung in 2 patients and lymph nodes in 1 patient (Table 2). In 6 ICC patients, 3 showed tumor recurrence, and the site was liver in 2 patients and peritoneal dissemination in 1 patient. No case showed the local recurrence. Early recurrence within 1 year after the surgery was observed in 1 ICC patient and 1 HC patient. The times to recurrence ranged from 4 to 40 months (median, 21.5 months). Three patients who received adjuvant S1 chemotherapy showed no early recurrence. The median survival time (MST) of the 11 patients who underwent surgery was 37 months, and the overall 1-, 2-, and 5-year survival rates were 80.8, 70.7 and 23.6%, respectively (Table 1, Fig. 3). Of the 4 patients who did not undergo surgery, 3 died of the primary disease, and the MST was 10 months. The overall 1- and 2-year survival rates were 37.5 and 0%, respectively. Patients who received radical surgery had significantly longer survival time than those who were unable to receive surgery (p = 0.027). Discussion Only a few previous reports have described CRT for unresectable locally advanced cholangiocarcinoma and subsequent surgery [ 10, 11 ]. McMasters et al. first reported the case of 9 patients who underwent preoperative CRT for initially unresectable extrahepatic cholangiocarcinoma [10]. Three of these 9 patients had a pathologic complete response, and the remainder showed varying degrees of histologic response. R0 resection was achieved in all 9 patients. Nelson et al. reported that 11 (91%) of 12 patients who received neoadjuvant CRT underwent R0 resection.11 These conversion rates to the resectable group were much higher than that in previous report of gemcitabine chemotherapy (36.4%) [ 6 ], and therefore, we chose CRT. ICC ICC ICC ICC ICC ICC ICC HC HC HC HC HC HC HC HC Reason for CRT HV, IVC invasion Perineural invasion PV invasion HV invasion Perineural invasion Perineural invasion Perineural invasion Biliary infiltration PV & arterial invasion Biliary infiltration Perineural invasion PV & arterial invasion Perineural invasion Biliary infiltration Perineural invasion ? ? ? ? ? ? ? ? ? ? CDDP & CPT-11 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 S1 Tumor diameter* Status Survival* (months) DD AD DOD RFS DD DD AD RFS DD DD RFS DD RFS DD DD 104 58 52 Pt no. patient number; M male; F female; ICC intrahepatic cholangiocarcinoma; HC hilar cholangiocarcinoma; CRT chemoradiotherapy; HV hepatic vein; IVC inferior vena cava; PV portal vein; BD biliary drainage; PVE portal vein embolization; N/A not applicable; Tumor diameter* (cm) maximum tumor diameter before and after the radiation; PR partial response; SD stable disease; PD progressive disease, NC not changed; Unresectable1 unresectable due to distant metastases; Unresectable2 unresectable due to primary tumor progression; Unresectable3 unresectable due to deteriorated performance status, DD death by primary disease; DOD death by other disease; AD alive with recurrent disease; RFS relapse-free survival; Survival* survival period after chemoradiotherapy Although previous results demonstrated a reliable effect of CRT on advanced cholangiocarcinoma, the largest problem is the absence of a definition for unresectable cholangiocarcinoma. These reports use such terms as ‘‘unresectable,’’’ ‘‘borderline resectable,’’ or ‘‘advanced’’ to represent tumor aggressiveness, and the border between resectable and unresectable cholangiocarcinoma remains unclear. Unlike pancreatic cancer, for which borderline resectable and unresectable cancers are clearly defined, there are no established definitions for unresectable cholangiocarcinoma. Therefore, the indication for surgery differs, depending on the institution and surgeons. Only 1 report from Chiba University has clearly described a definition of unresectable locally advanced cholangiocarcinoma [ 6 ]. In this report, the reasons for unresectability were defined as follows: local vascular invasion to be unable to reconstruct, extensive infiltration of the bile duct to be unable to reconstruct, extensive infiltration of the bile duct to be unable to achieve a curative resection, and insufficient liver volume [ 6 ]. In the present study, we used a definition that was similar with theirs, although our definition included broad extra-hepatic perineural invasion and excluded insufficient liver volume. These definitions were based on the favorable results of aggressive surgery without neoadjuvant therapy for locally advanced cholangiocarcinoma [ 15–17 ], and therefore, ipsilateral vascular invasion or contralateral vascular invasion to be able to reconstruct was not regarded as making the cholangiocarcinoma unresectable. In our series, about half of the CRT candidates had ICC and the remaining half had HC. Fourteen (93.3%) of 15 patients could accomplish the CRT, except for an 85-year n la e iso in eg lu ff omrah r u ifa le tis bd ro irev lreau tirsa t-raa ehm R ; n ) i s e e v t l u ta in r o (m e ; a m o n i c r a c o i g n a l o h c C I ; s u t a t s R - - P R - - - - - P m i D t l N a L ? ? ? ? ? ? ? ? ? ? ? c i g r R u s D B - ? ? ? - ? ? ? ? ? ? e* CRT and surgery CRT alone Time (months) old patient with deteriorated performance status. In 85.7% of the patients with ICC, tumor shrinkage was observed after CRT, and 71.4% of the patients were reclassified into the resectable group. Similarly, 75.0% of the patients with HC were reclassified into the resectable group. Overall, 11 (73.3%) of 15 patients were able to receive radical surgery after CRT. The most striking and unique result in this study is that radical surgery could be performed after CRT in 4 of the 7 patients with broad extra-hepatic perineural invasion extending around the proper hepatic artery and common hepatic artery. Except for 2 patients with PD and 1 patient with deteriorated performance status, remaining 4 of 7 patients with broad extra-hepatic perineural invasion received exploratory laparotomy, although no patient showed apparent shrinkage of perineural invasion on CT images after CRT. Radical surgery could be performed in all these 4 patients, resulting in 2 survivors longer than 3 years. CRT might provide an opportunity for radical surgery in patients with broad extra-hepatic perineural invasion, if distant metastases are absent. After CRT, the short-term outcomes of major hepatectomy with bile duct and vascular reconstruction were acceptable. No local recurrence was observed after the surgery, although R1 resection occurred in 2 (18.2%) patients. The comparison of post-CRT survival rates between resectable and unresectable patients indicated that surgical resection after CRT might be beneficial for initially unresectable locally advanced cholangiocarcinoma. As another therapeutic strategy for HC or ICC, some reports have described the utility of neoadjuvant CRT and subsequent liver transplantation [ 18, 19 ]. This strategy had essentially limited to cholangiocarcinoma of an early stage, without lymph node metastases or local extension because of organ shortage, frequent disease recurrence, and risk of immunosuppression [5]. Further, the majority of transplantation for neoplastic disease is performed for hepatocellular carcinoma or hepatoblastoma in Japan, and the procedure for cholangiocarcinoma has scarcely performed. However, Rayer et al. recently reported a case of huge unresectable ICC case with multiple intrahepatic metastases, which was significantly downstaged by a multimodal therapy including intra-arterial yttrium-90 radioembolization, allowing liver transplantation and subsequent recurrence-free survival for 3 years [ 20 ]. They described that chemotherapy with yttrium-90 radioembolization is an effective downstaging method for initially unresectable ICC cases [ 21 ]. Combination of yttrium-90 radioembolization and subsequent transplantation is thought to be one of the therapeutic options for unresectable ICC. This study has the following limitation: The clinical utility of CRT for unresectable locally advanced cholangiocarcinoma could not be demonstrated sufficiently because of the small number of cases and the retrospective nature of this study. The superiority of CRT to chemotherapy for such patients has not been proved. To resolve these issues, a multicenter randomized controlled trial using the definite criteria of the unresectable cholangiocarcinoma is needed. In conclusion, CRT allowed patients with initially unresectable locally advanced cholangiocarcinomas to be reclassified as surgical candidates in a substantial proportion. Further, the patients who underwent surgery had a significantly better survival rate than the patients who did not undergo surgery. CRT might be one of the treatment options for patients with initially unresectable locally advanced cholangiocarcinoma. Compliance with ethical standards Conflict of interest Tatsuaki Sumiyoshi and co-authors have no conflict of interest to declare. 1. Vauthey JN , Blumgart LH ( 1994 ) Recent advances in the management of cholangiocarcinomas . Semin Liver Dis 14 : 109 - 114 2. Aljiffry M , Walsh MJ , Molinari M ( 2009 ) Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990 - 2009 . World J Gastroenterol 15 : 4240 - 4262 3. Taylor-Robinson SD , Foster GR , Arora S et al ( 1997 ) Increase in primary liver cancer in the UK, 1979 - 94 . Lancet 350 : 1142 - 1143 4. Patel T ( 2001 ) Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States . Hepatology 33 : 1353 - 1357 5. Hong JC , Jones CM , Duffy JP et al ( 2011 ) Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center . Arch Surg 146 : 683 - 689 6. Kato A , Shimizu H , Ohtsuka M et al ( 2013 ) Surgical resection after downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer: a retrospective single-center study . Ann Surg Oncol 20 : 318 - 324 7. Nakeeb A , Pitt HA , Sohn TA et al ( 1996 ) Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors . Ann Surg 224 : 463 - 475 8. Nathan H , Aloia TA , Vauthey JN et al ( 2009 ) A proposed staging system for intrahepatic cholangiocarcinoma . Ann Surg Oncol 16 : 14 - 22 9. Valle J , Wasan H , Palmer DH et al ( 2010 ) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer . ABC-02 Trial Investigators . N Engl J Med 362 : 1273 - 1281 10. McMasters KM , Tuttle TM , Leach SD et al ( 1997 ) Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma . Am J Surg 174 : 605 - 609 11. Nelson JW , Ghafoori AP , Willett CG et al ( 2009 ) Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma . Int J Radiat Oncol Biol Phys 73 : 148 - 153 12. Kim YI , Park JW , Kim BH et al ( 2013 ) Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advancedstage unresectable intrahepatic cholangiocarcinoma . Radiat Oncol 8 : 292 13. Shirasaka T , Shimamoto Y , Ohshimo H et al ( 1996 ) Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators . Anticancer Drug 7 : 548 - 557 14. Uesaka K , Boku N , Fukutomi A et al ( 2016 ) Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01) . Lancet 388 : 248 - 257 15. Ebata T , Nagino M , Kamiya J et al ( 2003 ) Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases . Ann Surg 238 : 720 - 727 16. Igami T , Nishio H , Ebata T et al ( 2010 ) Surgical treatment of hilar cholangiocarcinoma in the ''new era'': the Nagoya University experience . J Hepatobiliary Pancreat Sci 17 : 449 - 454 17. Nagino M , Ebata T , Yokoyama Y et al ( 2013 ) Evolution of surgical treatment for perihilar cholangiocarcinoma: a singlecenter 34-year review of 574 consecutive resections . Ann Surg 258 : 129 - 140 18. Rea DJ , Heimbach JK , Rosen CB et al ( 2005 ) Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma . Ann Surg 242 : 451 - 461 19. Darwish Murad S , Kim WR , Harnois DM et al ( 2012 ) Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers . Gastroenterology 143 : 88 - 98 20. Rayar M , Levi Sandri GB , Houssel-Debry P et al ( 2016 ) Multimodal therapy including Yttrium-90 Radioembolization as a bridging therapy to liver transplantation for a huge and locally advanced intrahepatic cholangiocarcinoma . J Gastrointestin Liver Dis 25 : 401 - 454 21. Rayar M , Sulpice L , Edeline J et al ( 2015 ) Intra-arterial yttrium90 radioembolization combined with systemic chemotherapy is a promising method for downstaging unresectable huge intrahepatic cholangiocarcinoma to surgical treatment . Ann Surg Oncol 22 : 3102 - 3108


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2Fs00268-018-4558-1.pdf

Tatsuaki Sumiyoshi, Yasuo Shima, Takehiro Okabayashi, Yuji Negoro, Yasuhiro Shimada, Jun Iwata, Manabu Matsumoto, Yasuhiro Hata, Yoshihiro Noda, Kenta Sui, Taijiro Sueda. Chemoradiotherapy for Initially Unresectable Locally Advanced Cholangiocarcinoma, World Journal of Surgery, 2018, 1-9, DOI: 10.1007/s00268-018-4558-1