Highlights from the First Annual Cholangiocarcinoma Summit, October 2019
At the First Annual Cholangiocarcinoma Summit, presenters discussed recent advances in the management of patients with cholangiocarcinoma (CCA).
Surgery for hilar CCA, or Klatskin tumor, is dependent on the extent of the disease. The Bismuth-Corlette classification considers the spread of the tumor, along the biliary tree, and is based on the extent of ductal infiltration. Typically, tumors at stage I are considered resectable. Tumors at stage IV were traditionally thought to be unresectable, as they had spread to the bilateral second-order biliary radicals.
The goal of resection in patients with hilar CCA is a margin-negative resection, leaving at least 2 contiguous liver segments with adequate perfusion and biliary drainage. The surgery typically starts with a diagnostic laparoscopy, followed by a portal lymphadenectomy for staging, and then the removal of the bile duct, involved liver, and the caudate lobe, depending on the tumor location. A portal vein resection is then performed, if necessary, followed by reconstruction. Diagnostic laparoscopy is a critical aspect of the procedure.
The Blumgart preoperative clinical T-staging system for hilar CCA is defined by the radial and longitudinal extent of a tumor. In a series of 380 patients at Memorial Sloan Kettering Cancer Center in New York City, fewer than half of all individuals who were staged underwent curative resection.1 Most of these patients were found to be inoperable or with advanced disease. The median overall survival (OS) was 39 months, with a 5-year survival rate of 37.5%.1 Patients who underwent a margin-positive resection had similarly poor survival to those who were not resected.
In patients with intrahepatic CCA, the goals of resection are the same as with surgery for hilar CCA. The procedure begins with a diagnostic laparoscopy, followed by a portal lymphadenectomy, which is a new paradigm shift, as this was not performed routinely as recently as a few years ago. Typically, a biliary resection is not necessary unless the tumor involves the hilum.
Despite curative treatment, approximately 60% of patients with intrahepatic CCA will experience recurrence, typically at a median of 2 years.2 Most recurrences occur within the liver, which raises the question of whether patients with a margin-negative resection should receive adjuvant therapy or liver-directed therapy.
Surgery for distal CCA is similar to that of the Whipple procedure for patients with pancreatic cancer. The liver is not involved in this surgery. The major morbidity in distal CCA is associated with pancreatic reconstruction.
Minimally invasive surgery
Minimally invasive liver resection has lagged behind minimally invasive surgery for other indications because of the technical difficulty involved, the potential for significant blood loss, the complexity of the case, the reconstruction that is most often required, and the lack of dedicated training programs at most academic institutions. Over the past decade, however, the minimally invasive approach for hepatobiliary resections has been increasing.
Some of the factors that have allowed for adoption of this surgery include the introduction of endoscopic mechanical staplers, the Cavitron ultrasonic surgical aspirator, the TissueLink dissecting sealer, and the effect of pneumoperitoneum combined with low central venous pressure, which has limited blood loss and has improved patient outcomes.3
Comparative clinical trials of minimally invasive liver surgery and open surgery include the following:
- A double-blind, randomized trial of laparoscopic versus open left lateral sectionectomy plus an enhanced recovery program showed no differences between the 2 procedures with respect to length of hospital stay, overall morbidity/mortality, and hospital readmission rates at an interim analysis4
- In a comparison of minimally invasive (laparoscopic) surgery versus an open approach of parenchyma-sparing hepatectomy (ie, <3 segments), the minimally invasive approach was associated with a shorter length of hospital stay, thus resulting in a more cost-effective method5
- Another trial compared laparoscopic with open hepatectomy in patients with Child’s A cirrhosis and a solitary tumor of <5 cm. The minimally invasive treatment arm experienced a significantly shorter operative time and shorter duration of hospital stay (P <.001 for both). The secondary outcomes of blood loss, complications/readmission rates, 30-day mortality rates, and recurrence rates were similar with both approaches.6
In patients with perihilar CCA, the challenges associated with the use of minimally invasive surgery involve the fact that the procedure is considered highly demanding because of the proximity of these tumors to the portal vein and hepatic artery. The caudate lobectomy is also technically challenging. Morbidity and mortality are high compared with other modalities of hepatobiliary resections. The extremely difficult nature of the procedure and the fear of oncologic inefficiency have limited the adoption of the minimally invasive surgical approach for perihilar CCA.
The use of minimally invasive surgery in patients with perihilar CCA has not been well-studied. A systematic review of 21 studies, with the largest series including 44 patients, reported a conversion rate to open surgery of 4.9%.7 The average length of hospital stay across all the studies was 10.8 days (range, 3-58 days). On pooled analysis, the rate of postoperative morbidity was 23.8% and the mortality rate at 90 days was 3.2%, which are far lower than the rates reported for open procedures.7 Negative resection margin (R0) was attained in almost 80% of the patients. Limitations of this systematic review include the fact that 6 of the studies did not report follow-up after hospital discharge and the possibility of selection bias.7
The National Cancer Database was used to examine oncologic outcomes among 2309 patients with intrahepatic CCA who underwent 1997 open versus 312 laparoscopic hepatic resections between 2010 and 2015.8 Nodal evaluation, which was performed in 58% of all patients evaluated, was significantly more common among patients who underwent open versus minimally invasive surgery (61% vs 39%, respectively; P <.001).8 Adjuvant chemotherapy and radiation was used more frequently in patients who had ≥1 lymph nodes evaluated.8 Based on these findings, it appears that an inability to establish nodal staging is associated with an inaccurate prognosis and thus can influence the use of adjuvant therapy in patients with intrahepatic CCA.
Surgical resection is the only curative option for intrahepatic CCA, but most patients are not candidates for this procedure. In addition, most patients die of intrahepatic tumor–related complications. Liver-directed therapies to control intrahepatic progression may be appropriate for some patients.
Liver-directed therapies can be used in patients with resectable and unresectable metastatic disease. Ablation technologies include radiofrequency ablation and microwave ablation (MWA).
Ablation has been compared with resection in 2 studies of patients with recurrent intrahepatic CCA. In a comparison of MWA and surgical resection, no difference in 5-year OS was observed between the groups, but the group undergoing surgery had a longer procedure time, a longer length of hospital stay, greater blood loss, a higher complication rate, and a higher cost.9 In a study that compared thermal ablation with surgical resection, no differences in OS and disease-free survival were reported between the groups.10 The rate of major complications, however, was significantly higher in the resection group than in the thermal ablation group (P <.001).10 In patients with large, recurrent tumors (ie, >3 cm in diameter), OS was significantly higher in those undergoing resection (P = .037).10
The use of radioembolization was assessed in a systematic review of 9 relatively small observational studies that included a total of 224 patients.11 Patients with the mass-forming type of intrahepatic CCA had a significantly better median OS than those with the infiltrative type (19.9 months vs 8.1 months, respectively).11 Moreover, patients with treatment-naïve CCA had a longer OS than those who had received therapy prior to radioembolization. Patients who were receiving concurrent chemotherapy had significantly better OS compared with those who were not receiving chemotherapy (19.5 months vs 5.5 months, respectively; P = .042).11
The largest published series of patients undergoing radioembolization for intrahepatic CCA is from a retrospective study of all individuals (N = 85) who were not surgical candidates and were ineligible for chemotherapy.12 The median OS from diagnosis was 21.4 months (95% confidence interval [CI], 16.6-28.4), and the median OS from treatment with radioembolization was 12.0 months (95% CI, 8.0-15.2).12 No 30-day mortality was reported following radioembolization therapy. Survival was assessed based on imaging characteristics; no difference could be detected in median OS between hypo-enhancing or hyper-enhancing tumors or between mass-forming or infiltrative tumors.12
Hepatic artery infusion pump
Intrahepatic CCA is a primary liver tumor that is often locally advanced but not metastatic at the time of presentation. Importantly, these tumors derive their blood supply predominantly from the hepatic arterial system, providing the rationale behind use of a hepatic arterial infusion pump. Floxuridine (FUDR) for use in the infusion pump is a 5-fluorouracil (5-FU) analog with extensive first-pass liver uptake and high efficacy against intrahepatic CCA. FUDR has high hepatic exposure, which is 100-fold to 400-fold higher than that of other agents used for hepatic arterial infusion.13
A phase 2 study of hepatic arterial infusion of FUDR in combination with systemic gemcitabine and oxaliplatin in 38 patients with unresectable, nonmetastatic intrahepatic CCA demonstrated a 58% partial radiographic response rate and an 84% disease control rate at 6 months.14 Overall, 4 patients experienced a sufficient response to undergo surgical resection. With a median follow-up of 30.5 months, the median progression-free survival (PFS) was 11.8 months and the median OS was 25.0 months.14 Toxicities were manageable and tolerable, with elevated levels of liver enzymes being the most common grade ≥3 adverse event.14
Role of radiation
In patients with intrahepatic CCA, palliative doses of radiation have been replaced by ablative radiotherapy doses over time, as imaging guidance, proton beam radiation, and intensity-modulated radiation therapy became available. This has resulted in clear improvements in patient outcomes, with local tumor control rates as high as 80% and 4-year OS as high as 75%.15 Of the patients who received lower doses of radiation, 89% died of tumor-related liver failure.15
In a phase 2 study, 37 patients were treated with 3 to 5 weeks of ablative radiation over 3+ years, typically in a later-line setting following hepatic arterial infusion pump therapy or chemotherapy with progression.16 Overall, 60% of the patients had extrahepatic disease. Local tumor PFS was 80% and median OS was 33.5 months.16
An ablative dose of radiation can be administered over 1 week, 2 weeks, 3 weeks, or 5 weeks. The choice is dependent on the size of the tumor and how much of the liver and/or gastrointestinal tract needs to be protected.
Gallbladder cancer and intrahepatic CCA have a high risk for distant metastases. Moreover, the likelihood of an isolated local recurrence following surgery is low, which limits the role of adjuvant chemoradiation for this population.
Most studies of adjuvant radiation for patients with extrahepatic CCA demonstrated an improvement in local-regional control, with a suggestion of an improvement in OS in some series. The caveat with respect to single-institution studies is the potential for patient selection bias: patients with better performance status may be selected for chemoradiation.
A meta-analysis of 20 studies including 6712 patients found that adjuvant radiation therapy appears to have a significant benefit only in those with positive resection margin (R1), regardless of disease site, in the end point of OS.17 In contrast, radiation therapy was associated with nonsignificant odds of harm among patients with R0 resection.17
Prospective data from the single-arm, phase 2 Southwest Oncology Group (SWOG) S0809 study of high-risk patients with extrahepatic CCA or gallbladder cancer were evaluated. Patients were treated with gemcitabine and capecitabine for 4 months, followed by chemoradiation.18 Rates of 2-year OS were promising, exceeding 60%. On subgroup analysis, the addition of radiation nearly negated the adverse impact of R1. The overall local failure rate was 21% in the distal bile duct. For hilar CCA, the local failure rate was 23%.18
The National Comprehensive Cancer Network guideline for the management of extrahepatic CCA lists chemoradiation as a postresection option in patients with R0 or R1 resection, with similar recommendations for gallbladder cancer.19 Chemoradiation is not recommended in the R0 setting in patients with intrahepatic CCA.19
Based on the observation that a select few patients with early-stage disease achieved long-term survival, combined with the finding that radiation provided palliation and, in rare cases, prolonged survival, the Mayo Clinic team in Rochester, MN, initiated a radiation protocol for patients with unresectable hilar CCA.20,21 This protocol combines neoadjuvant radiation and chemotherapy, in the form of external beam radiotherapy with bolus 5-FU, followed by brachytherapy and oral capecitabine, a formal exploratory laparotomy to rule out metastases or local extension of the tumor (which would preclude complete resection), then orthotopic liver transplant (OLT) either from a living donor or from a deceased donor.21 Staging is important to detect peritoneal disease and rule out node-positive disease.
Eligibility criteria include a malignant-appearing stricture and ≥1 of the following: (1) malignant cytology or histology, (2) an elevated CA 19-9 without cholangitis, or (3) polysomy detected by fluorescence in situ hybridization (FISH). The cancer should be located primarily above the cystic duct. The cancer must be unresectable (de novo CCA) or cancer arising in the setting of primary sclerosing cholangitis (PSC). Excluded patients were those with a mass >3 cm into the parenchyma, those who have undergone prior attempted resection with violation of the tumor plane, and those in whom transperitoneal biopsy was performed.22 Combined neoadjuvant therapy plus liver transplantation achieved favorable results for unresectable patients with perihilar CCA.
Results from a study of 211 patients who proceeded to liver transplant show 69% survival at 5 years posttransplant and 62% at 10 years.23 Patients with PSC had superior outcomes, possibly because they had been captured earlier. A histologic response to the neoadjuvant therapy is one of the keys to a successful outcome, the reason for which is not understood. When adjusted for age, stage, and PSC, residual tumor was still the key predictor of recurrence.23
Liver transplant may also be appropriate for patients with potentially resectable de novo hilar CCA. The experience at 10 US centers of patients with perihilar CCA undergoing resection versus transplant reveals superior 3-year survival (72% vs 33%, respectively) and 5-year survival (64% vs 18%, respectively) with transplantation.24 Resection for the patients who met the transplant criteria was associated with worse survival.24
Intrahepatic CCA. OLT can be performed in patients with unresectable intrahepatic CCA, with excellent outcomes, and may exhibit survival advantages compared with resection.
In a single-center, comparative analysis of resection versus OLT for intrahepatic or hilar CCA of >24-year duration, patients who underwent OLT fared much better than did those who underwent surgical resection.25 Among those undergoing OLT, neoadjuvant plus adjuvant therapy significantly improved outcomes compared with adjuvant therapy alone or no adjuvant therapy (P = .03), with OS approaching 60% in the neoadjuvant/adjuvant therapy group.25 Factors that predicted worse survival outcomes on multivariate analysis were hilar CCA, multifocal tumors, perineural invasion, and resection compared with OLT as the treatment modality. Tumor size was not a predictor of poor outcome.25
Liver transplant for “very early” intrahepatic CCA (ie, a single tumor ≤2 cm) is associated with a low risk for recurrence.26 Among patients who had a transplant for hepatocellular carcinoma or decompensated cirrhosis who had intrahepatic CCA at explant pathology, the 1-, 3-, and 5-year cumulative recurrence risks were 7%, 18%, and 18%, respectively, after a median follow-up of 35 months in those with very early intrahepatic CCA. The 1-, 3-, and 5-year survival rates in this patient population were 93%, 84%, and 65%, respectively.26
According to the Methodist–MD Anderson (Houston, TX) protocol, 6 months’ duration of stability under neoadjuvant therapy may be an appropriate surrogate marker for the selection of patients with biologically favorable disease for OLT.27 Imaging is repeated every 3 months and has to demonstrate stable or regressing disease. Among 21 patients with intrahepatic CCA referred for OLT, 6 received transplantation.27 Most tumors were stage T2; the median maximum lesion size was 7.4 cm, and the median total diameter of the lesions was 10.4 cm. Explant characteristics were as follows: the number of lesions was 3, the median maximum lesion size was 6.0 cm, and the median total diameter of the lesions was 8.5 cm. The 5-year survival rate following OLT was 83.3%.27
- Matsuo K, Rocha FG, Ito K, et al. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg. 2012;215:343-355.
- Blechacz B. Cholangiocarcinoma: current knowledge and new developments. Gut Liver. 2017;11:13-26.
- Poon RTP. Current techniques of liver resection. HPB (Oxford). 2007;9:166-173.
- van Dam RM, Wong-Lun-Hing EM, van Breukelen GJ, et al; ORANGE II Study Group. Open versus laparoscopic left lateral hepatic sectionectomy within an enhanced recovery ERAS® programme (ORANGE II – trial): study protocol for a randomised controlled trial. Trials. 2012;13:54. doi: 10.1186/1745-6215-13-54.
- Fretland ÅA, Dagenborg VJ, Bjørnelv GMW, et al. Laparoscopic versus open resection for colorectal liver metastases: the OSLO-COMET randomized controlled trial. Ann Surg. 2018;267:199-207.
- El-Gendi A, El-Shafei M, El-Gendi S, Shawky A. Laparoscopic versus open hepatic resection for solitary hepatocellular carcinoma less than 5 cm in cirrhotic patients: a randomized controlled study. J Laparoendosc Adv Surg Tech A. 2018;28:302-310.
- Franken LC, van der Poel MJ, Latenstein AEJ, et al. Minimally invasive surgery for perihilar cholangiocarcinoma: a systematic review. J Robot Surg. 2019;13:717-727.
- Martin SP, Drake J, Wach MM, et al. Laparoscopic approach to intrahepatic cholangiocarcinoma is associated with an exacerbation of inadequate nodal staging. Ann Surg Oncol. 2019;26:1851-1857.
- Xu C, Li L, Xu W, et al. Ultrasound-guided percutaneous microwave ablation versus surgical resection for recurrent intrahepatic cholangiocarcinoma: intermediate-term results. Int J Hyperthermia. 2019;36:351-358.
- Zhang S-J, Hu P, Wang N, et al. Thermal ablation versus repeated hepatic resection for recurrent intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2013;20:3596-3602.
- Cucchetti A, Cappelli A, Mosconi C, et al. Improving patient selection for selective internal radiation therapy of intra-hepatic cholangiocarcinoma: a meta-regression study. Liver Int. 2017;37:1056-1064.
- Gangi A, Shah J, Hatfield N, et al. Intrahepatic cholangiocarcinoma treated with transarterial yttrium-90 glass microsphere radioembolization: results of a single institution retrospective study. J Vasc Interv Radiol. 2018;29:1101-1108.
- Kelly RJ, Kemeny NE, Leonard GD. Current strategies using hepatic arterial infusion chemotherapy for the treatment of colorectal cancer. Clin Colorectal Cancer. 2005;5:166-174.
- Cercek A, Boerner T, Tan BR, et al. Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2019 Oct 31. doi: 10.1001/jamaoncol.2019.3718. [Epub ahead of print].
- Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy does lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol. 2016;34:219-226.
- Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016;34:460-468
- Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30:1934-1940.
- Ben-Josef E, Gutrhie KA, El-Khoueiry AB, et al. SWOG S0809: a phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33:2617-2622.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Hepatobiliary Cancers. Version 1.2018—February 14, 2018. https://oncolife.com.ua/doc/nccn/Hepatobiliary_Cancers.pdf. Accessed December 9, 2019.
- Gulamhusein A, Sanchez W. Liver transplantation in the management of perihilar cholangiocarcinoma. Hepat Oncol. 2015;2:409-421.
- De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoradiation for cholangiocarcinoma. Liver Transpl. 2000;6:309-316.
- Darwish Murad S, Kim WR, Therneau T, et al. Predictor of pre-transplant dropout and post-transplant recurrence in patients with prior cholangiocarcinoma. Hepatology. 2012;56:972-981.
- Heimbach J. Resection or transplantation for perihilar cholangiocarcinoma: yes. Slide deck presented at: 13th Annual Conference of the International Liver Cancer Association (ILCA); September 20-22, 2019; Chicago, IL. https://ilca2019.org/wp-content/uploads/2019/10/heimbach-ILCA-2019-resection-or-transplantation-CCA.pptx. Accessed December 9, 2019.
- Ethun CG, Lopez-Aguiar AG, Anderson DJ, et al. Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease. Ann Surg. 2018;267:797-805.
- Hong JC, Jones CM, Duffy JP, et al. Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. Arch Surg. 2011;146:683-689.
- Sapisochin G, Facciuto M, Rubbia-Brandt L; iCCA International Consortium. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology. 2016;64:1178-1188.
- Lunsford KE, Javle M, Heyne K, et al; Methodist–MD Anderson Joint Cholangiocarcinoma Collaborative Committee (MMAJCCC). Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol Hepatol. 2018;3:337-348.