Surgery for Cholangiocarcinoma: Before and After

December 2019 Highlights from the First Annual Cholangiocarcinoma Summit - Cholangiocarcinoma


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At the First Annual Cholangiocarcinoma Summit, presenters discussed recent advances in the management of patients with cholangiocarcinoma (CCA), including new surgical approaches, the expanding role of liver-directed therapies, radiation, and transplantation, and more effective sequencing of neoadjuvant and adjuvant therapies.

Surgery

Hilar cholangiocarcinoma

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 in one dimension, along the biliary tree, and is based on the extent of ductal infiltration. Typically, tumors in the Bismuth I stage 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, as it may identify disease features not detected on imaging.

The Blumgart preoperative clinical T-staging system for hilar CCA, which was devised to determine resectability, is defined by the radial and longitudinal extent of a tumor. In a series of 380 patients at Memorial Sloan Kettering Cancer Center (MSKCC) 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.

Intrahepatic cholangiocarcinoma

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.

Distal cholangiocarcinoma

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, implementation of 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

Perihilar cholangiocarcinoma

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 those related to other modalities of hepatobiliary resections. The extremely difficult nature of the procedure and the fear of oncologic inefficiency have thus far limited the adoption of the minimally invasive surgical approach for the treatment of 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 of 142).7 The average length of hospital stay across all the studies was 10.8 days (range, 3-58 days).7 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

Oncologic outcomes

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.

Liver-Directed Therapies

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. The use of liver-directed therapies to control intrahepatic progression and thus improve survival may be appropriate for some patients.

A multitude of liver-directed therapies, including different forms of ablation, embolization technologies, and hepatic artery chemoperfusion, is available. However, no prospective, randomized trials of liver-directed therapies are available, and retrospective studies to date have enrolled small numbers of patients and a heterogeneous patient population.

Liver-directed therapies can be used in patients with both resectable and unresectable metastatic disease. Ablation technologies include radiofrequency ablation and microwave ablation (MWA).

Ablation

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

Based on studies of ablation, the following conclusions can be drawn:

  • Ablation can be considered if the lesion is <3 cm
  • A wide ablation zone (>1 cm) should be used
  • Combination therapy with embolization may be considered with larger tumor size
  • Ablation is preferred for patients who are not surgical candidates because of comorbidities or lesion location, since surgery is still the standard of care
  • Ablation is likely a better approach for patients who have recurrent intrahepatic CCA after a surgical resection.

Radioembolization

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

Large-scale prospective clinical trials are warranted, to better define the role of liver-directed therapies.

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.

With both gallbladder cancer and intrahepatic CCA, there is a high risk for developing distant metastases. Moreover, in such patients, the likelihood of an isolated local recurrence following surgery is low, which limits the role of adjuvant chemoradiation for this indication.

Radiation in the adjuvant setting

Radiation therapy is controversial in the adjuvant setting for biliary tract cancer. In patients with CCA, the data regarding radiation are of poor quality, consisting mainly of single-institution retrospective reviews; large databases with limited single patient details; and a mix of patients with hilar, distal bile duct, and gallbladder cancers.

Extrahepatic cholangiocarcinoma

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 (NCCN) guideline for the management of extrahepatic CCA lists chemoradiation as a postresection treatment 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

Liver Transplantation

Hilar cholangiocarcinoma

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 transplantation show 69% survival at 5 years posttransplant and 62% at 10 years.23 Patients with PSC had superior outcomes, possibly because they had been on surveillance and were captured earlier. A histologic response to the neoadjuvant therapy is one of the keys to a successful outcome, the reason for which is not well understood. When adjusted for age, stage, and presence of PSC, residual tumor was still the key predictor of recurrence.23

Liver transplantation 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. Prospective trials are warranted and justified.24

Intrahepatic cholangiocarcinoma

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 transplantation for “very early” intrahepatic CCA (ie, a single tumor ≤2 cm) was shown to be associated with a low risk for recurrence.26 Among a group of patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis who were found to have intrahepatic CCA at explant pathology, the 1-, 3-, and 5-year cumulative risks for recurrence were 7%, 18%, and 18%, respectively, after a median follow-up of 35 months in those with very early intrahepatic CCA. Moreover, the 1-, 3-, and 5-year survival rates in this same 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 might 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

Before Surgery: Sequencing Neoadjuvant Therapy

Neoadjuvant treatment has both advantages and disadvantages. Although more patients will receive treatment, the risk for overtreatment is real, as observed in those with limited-stage disease. Neoadjuvant therapy may obviate surgery in those who progress rapidly because of poor biology, but the downside is that it will delay potentially beneficial surgery and some patients may not be able to proceed to surgery at all.

Disease biology appears critical for patient selection for neoadjuvant therapy. In the BILCAP study, treatment with neoadjuvant capecitabine had no effect on survival with R1 resection but improved survival with R0 resection.28 Whether R1 resection reflects disease biology or simply the size of the cancer itself is uncertain. An apparent lack of benefit to neoadjuvant treatment was observed in patients with perihilar CCA, whereas those with extrahepatic CCA appeared to benefit despite a similar R1 resection rate.

The goal of neoadjuvant therapy is to eradicate micrometastases and to improve the rate of margin-negative resection in patients with technically resectable disease. Data on neoadjuvant treatment in patients with CCA are sparse. The greatest obstacle to conducting clinical trials on neoadjuvant therapy in CCA is its rarity, so multi-institutional, multinational collaboration is warranted. Furthermore, since most intrahepatic and hilar CCAs are not resectable at presentation, patients cannot be enrolled in a neoadjuvant trial. Finally, a preoperative tissue diagnosis is usually required to enroll in a trial, which can be difficult to obtain in patients with hilar CCA.

The largest experience with neoadjuvant therapy in CCA comes from the selection of patients for transplantation who have already met transplant inclusion criteria. The goal of neoadjuvant therapy in this setting is to eradicate micrometastatic disease and help to select those patients who will achieve a better outcome with transplant. The challenges associated with neoadjuvant therapy in the resectable setting are numerous, including preoperative tissue diagnosis and the need for SpyGlass endoscopy or FISH analysis as a complement to biopsy to make the diagnosis.

In the intrahepatic resectable CCA setting, 5-year OS is 31%, so the room for improvement with neoadjuvant therapy is considerable.29 Clinical trials of neoadjuvant therapy in intrahepatic CCA were initially conducted in the metastatic setting, but it took 4 years to accrue the data and an additional 3 to 5 years for follow-up. Therefore, the lag of extrapolation of data to patients with resectable disease was about a decade.

An ongoing study is testing the hypothesis that neoadjuvant therapy with gemcitabine, cisplatin, and nab-paclitaxel is feasible, will increase resectability rates, and will improve recurrence-free survival and OS for patients with resectable oncologically high-risk intrahepatic CCA.30

After Surgery: Sequencing Adjuvant Therapy

A clear consensus on the standard of care for patients following resection for biliary tract cancer has been difficult to achieve. For many years, a lack of collaboration and the use of small retrospective studies have limited the ability to definitively determine a benefit for treatment. Recent larger trials have been conducted with more statistical rigor and are having an impact on the care of patients with biliary tract cancers.

Pooled data from a 2012 systematic review/meta-analysis of 20 studies (mentioned earlier in this section) that included 6712 patients showed a trend to improved survival with adjuvant therapy in the treatment of biliary tract cancer, specifically for R1 resection, with a suggestion that chemotherapy or chemoradiation was better than radiation alone.17

The best prospective data for the use of adjuvant therapy in patients with biliary tract cancer come from the randomized, controlled, multicenter, phase 3 BILCAP study.31 Although capecitabine did not improve OS over observation in the intention-to-treat population, “the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care.”31

No controlled trials have demonstrated a benefit with adjuvant chemoradiation over surgery alone in patients with biliary tract cancer, although many retrospective studies suggest superior outcomes with adjuvant therapy. Adjuvant therapy may have a role in those patients with an incompletely resected tumor.

Extrahepatic cholangiocarcinoma

In a randomized study of patients with resected periampullary adenocarcinoma, participants were assigned to observation, adjuvant gemcitabine, or 5-FU/leucovorin.32 After adjustment for independent prognostic variables, chemotherapy was superior to observation with respect to OS. Because of the small number of patients with biliary cancer, the effect of treatment on survival in this group was not reported.32

Intrahepatic cholangiocarcinoma

In patients with intrahepatic CCA, adjuvant chemotherapy and chemoradiation improved outcomes in patients with positive margins or positive lymph nodes, but the benefit was absent in those with negative margins or negative lymph nodes. In the Taiwan Cancer Registry analysis, superior OS was achieved with chemoradiation compared with chemotherapy alone in patients with positive margins or stage III or IV intrahepatic CCA.33

“What I took away from this study the most is that the sequential chemotherapy followed by radiation therapy wasn’t as beneficial as the combination of chemotherapy with radiation,” one of the audience members noted.

Gallbladder cancer

In a phase 3, multicenter, prospective, randomized, controlled trial, surgery plus mitomycin C and infusional 5-FU improved 5-year OS in patients with resected gallbladder cancer, but the benefit appeared to be limited to patients deemed to have a “noncurative” resection.34 There was no benefit to adjuvant therapy in bile duct or ampullary cancers, regardless of the type of resection.

In patients with gallbladder cancer, the benefit of adjuvant chemoradiation appears to be modest, based on an analysis of the National Cancer Database.35 The best prospective data in this setting are from SWOG S0809, in which adjuvant capecitabine and gemcitabine followed by radiotherapy led to a high 2-year OS rate, with similar OS and local control in patients with R0 and R1 resections.18 A major limitation of SWOG S0809 was the lack of a concurrent control arm.18

Chorus Discussion

Chorus members were asked whether they offered local therapy to patients with intrahepatic CCA who were not candidates for surgery. More than half (55%) indicated that they did. When asked about their preferred local therapeutic modality for patients with inoperable intrahepatic CCA, the audience was split evenly between ablative external beam radiation therapy administered at 100 Gy in 15 to 25 fractions and radioembolization with Y-90 (33% each), whereas 22% would opt for hepatic artery chemoperfusion and 11% would select conventional dose radiation therapy (50.4 Gy in 28 fractions). The chorus members emphasized the importance of an adequate dose of radiation to achieve maximum benefits if radiation is to be used in this setting.

The sequencing of systemic chemotherapy relative to liver-directed therapy for patients with localized, yet inoperable CCA was discussed, with one chorus member noting that 70% of patients receive chemotherapy prior to radioembolization, which improves survival compared with no chemotherapy. Another member commented that the sequencing of chemotherapy depends on the local treatment. For example, with hepatic arterial infusion, chemotherapy would be administered concurrently. The sequencing of local-regional therapy may also be important, as it could affect subsequent choices of local-regional therapy.

According to one chorus member, for nonsurgical candidates, one must differentiate between a nonsurgical candidate for resection and a nonsurgical candidate for transplant. “Obviously, transplant is making its way into those patients,” he stated. “We’re still going to resect patients if they have localized disease. Having said that, those modalities are going to be employed when you are unable to do a primary resection. We use these as temporizing measures, so which temporizing measure is better? With a multifocal T2 lesion, I probably would start thinking about a transplant.”

With intrahepatic CCA, targets for transplant depend on the ability to contain the tumor locally, noted another presenter. “Of patients who have liver disease only, without metastatic disease, chemotherapy is successful in containing the tumor about 50% of the time,” he indicated. “That gives us 50% of the patients with T2 nonmetastatic disease as potential targets for transplant.”

Selection is key to transplantation in hilar CCA as well, said another audience member “in that you need to exclude people with metastatic disease.”

References

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