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Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma

Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma
Literature review current through: May 2024.
This topic last updated: Jul 18, 2022.

INTRODUCTION — Cholangiocarcinomas are rare malignancies arising from the epithelial cells of the intrahepatic and extrahepatic bile ducts. Locally advanced cholangiocarcinoma encompasses a heterogeneous mix of patients who fit the following categories:

Locally advanced, categorically unresectable, but nonmetastatic disease at presentation, which may include patients with an isolated intrahepatic mass with imaging characteristics consistent with malignancy but not with hepatocellular cancer, and those without an apparent mass lesion who have a malignant biliary stricture, often with jaundice. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Preoperative assessment and criteria for resectability'.)

Microscopic and macroscopic residual disease following resection of either an intrahepatic or an extrahepatic cholangiocarcinoma.

The prognosis is typically measured in months, and their lives are characterized by rapid decline with symptoms of progressive biliary obstruction. The goals of palliative therapy are relief of symptoms (pain, pruritus, jaundice) and improvement in quality of life. There is no role for surgical debulking in these cases.

Nonsurgical local therapies (radiation therapy [RT], photodynamic therapy [PDT], local ablation, and hepatic arterial embolization) can be used to prolong the time to local failure (eg, in the setting of macroscopically positive margins only) or to palliate local symptoms such as pain or jaundice (eg, in the setting of categorically unresectable or recurrent disease). Systemic chemotherapy can also enhance disease control. Although most patients will be treated with the goal of palliation, select patients will have a sufficient response to neoadjuvant therapy to permit later resection.

Palliation of obstructive jaundice and antineoplastic treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma will be reviewed here. The epidemiology, pathology, classification, staging, clinical presentation, diagnosis, and surgical therapy for localized, potentially resectable disease, and adjuvant therapy and systemic therapy for advanced disease are discussed separately. (See "Clinical manifestations and diagnosis of cholangiocarcinoma" and "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma" and "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma" and "Systemic therapy for advanced cholangiocarcinoma".)

PATIENTS WITH OBSTRUCTIVE JAUNDICE — For palliation of jaundice in patients who have unresectable extrahepatic cholangiocarcinoma that was established either radiographically or laparoscopically, an endoscopically placed stent is preferred over surgical bypass for most patients, especially those with hilar tumors. Palliative surgical bypass should be limited to those who were found to have unresectable distal cholangiocarcinoma during exploratory laparotomy, or if stenting cannot be achieved for technical reasons, such as tumor location.

Stent placement versus surgical decompression — Palliation of jaundice can be accomplished with operative biliary-enteric bypass or with endoscopic/percutaneous stenting of the biliary tree. For most patients, nonoperative management is preferred.

Placement of a stent is generally preferred for long-term palliation since it is associated with similar rates of successful palliation and survival but less morbidity compared with the surgical approach [1-8]. Successful endoscopic deployment of a stent (or multiple stents as needed to span the malignant stricture) is possible in 70 to 100 percent of patients.

Palliative surgical bypass is typically only performed during an unsuccessful attempt at resection. Rarely, surgical bypass may be necessary in a jaundiced patient in whom stenting cannot be achieved for technical reasons, such as tumor location. Most often, the bypass is to the liver segment IV to II/III (figure 1) bile duct. In some cases, bypass to the segment V duct (figure 1) can be used for palliation of the right liver ductal system, but this is performed less frequently due to higher technical difficulty. (See "Surgical resection of lesions of the head of the pancreas", section on 'Palliative surgery'.)

In addition to the optimal approach to stent placement, other major issues include the use of plastic or metal (and bare versus covered) stents, the benefit of prophylactic antibiotics, and the benefit of photodynamic therapy (PDT) in conjunction with stent placement. (See "Endoscopic stenting for malignant biliary obstruction".)

Percutaneous versus endoscopic approach – In most institutions, an initial endoscopic attempt at biliary drainage is usually preferred if possible.

Retrospective series and at least two trials conducted in patients with obstructive jaundice from a malignant hilar obstruction (mainly proximal cholangiocarcinoma or gallbladder cancer) suggest that successful palliation of jaundice is more likely and rates of early cholangitis may be lower with a percutaneous, rather than endoscopic, approach to biliary drainage [9-11].

However, other complications may be more frequent (eg, bile leaks and bleeding), potentially increasing morbidity and mortality [10,12]. Furthermore, percutaneous stents are usually left to open drainage external to the body, at least initially, and this is often inconvenient to the patient. This subject is discussed in detail elsewhere. (See "Endoscopic stenting for malignant biliary obstruction".)

Unilateral versus bilateral stents – For patients with hilar obstruction and inoperable tumors or those who are being considered for neoadjuvant therapy, bilateral stents are preferred, when possible, in an attempt to maximize biliary drainage. For patients with potentially operable tumors, we lace unilateral stents to drain the future liver remnant.

For patients with hilar obstruction, whether to use unilateral or bilateral stents is debated. Studies comparing these approaches have reached variable conclusions. In many cases, unilateral stent placement will be adequate because only 25 to 30 percent of the liver needs to be drained to relieve jaundice [13]. However, unilateral drainage alone may not relieve jaundice completely and may increase the risk of cholangitis. Other studies have suggested that drainage of 50 percent of total liver volume may be more beneficial [14], and this may require bilateral stenting.

These are difficult decisions, especially in patients who are being managed palliatively. In practice, many endoscopists place bilateral stents (plastic or metal), when possible, in an attempt to maximize biliary drainage. However, it is often not possible. Preprocedure computed tomography (CT) and/or magnetic resonance cholangiopancreatography (MRCP) imaging is often used in an attempt to identify the dominant biliary system in the event that only one side can be drained endoscopically. (See "Endoscopic stenting for malignant biliary obstruction", section on 'Selecting a stent for palliative drainage'.)

Another issue is that we tend to avoid percutaneous stents, especially bilateral stents, in the palliative setting. They are difficult to internalize in patients who develop progressive disease, and the external draining catheter(s) can complicated end of life care.

Plastic versus metal stents – Endoscopic biliary decompression can be achieved using either plastic or expandable metal stents. A variety of plastic and metal stents, both covered and uncovered, are available. A systematic review concluded that neither stent type offered a survival advantage [15]. However, a subsequent randomized trial directly addressing this issue in patients with unresectable hilar cholangiocarcinoma concluded that metal stents provided better drainage, and prolongation of survival compared with plastic stents [16]. (See "Endoscopic stenting for malignant biliary obstruction", section on 'Types of biliary stents'.)

Major advantages of plastic stents are that they are inexpensive and the stent can be easily removed or exchanged. Plastic stents, however, eventually develop occlusion with sludge and/or bacterial biofilm, and maintaining biliary drainage with plastic stents usually requires repeated endoscopic retrograde cholangiopancreatographies. (See "Endoscopic stenting for malignant biliary obstruction", section on 'Plastic stents'.)

While metal stents extend the duration of stent patency (approximately 8 to 12 versus 2 to 5 months), they have significantly higher costs and may not be removable. Thus, the diagnosis of malignant disease must be firmly established before a metal stent is deployed.

In practice, plastic stents are often used to initially achieve drainage while the diagnostic workup is ongoing or when a metal stent cannot be inserted for technical reasons. The high occlusion rate of plastic (polyethylene) stents (average 42 percent) can be reduced by changing the stents every three to six months. An alternative approach is to wait for a complication before changing the stent since many patients will die of their disease before their stents become obstructed. However, patients are at risk of developing cholangitis when the stent becomes obstructed. The preferred approach for patients who are expected to live beyond a few months is to replace the plastic stent with a metal one as soon as is feasible.

Covered versus uncovered stents – Several trials have evaluated the differences in stent patency rates between covered and uncovered metal stents for the treatment of distal malignant biliary disease; despite showing significantly less tumor ingrowth, patency rates are not higher for covered stents. This can likely be explained by the many other etiologies of stent occlusion other than tumor ingrowth, including tumor overgrowth and stent obstruction from debris and biliary sludge. (See "Endoscopic stenting for malignant biliary obstruction", section on 'Adverse events' and "Pancreatic stenting at endoscopic retrograde cholangiopancreatography (ERCP): Indications, techniques, and complications", section on 'Adverse events'.)

For the treatment of distal malignant biliary obstruction, many endoscopists place uncovered (bare) metal stents in patients with an intact gallbladder. For patients who have undergone prior cholecystectomy, the choice of a covered versus uncovered stent is individualized given the location and geometry of the stenosis. Patients with extrinsic compression may be adequately treated with an uncovered stent, while those with intrinsic and/or papillary tumors may benefit from a covered stent in an attempt to minimize tumor ingrowth. Covered metal stents are only used for distal biliary strictures because, with hilar tumors, deployment may inadvertently result in occlusion of a major hepatic duct. This subject is discussed in detail elsewhere. (See "Endoscopic stenting for malignant biliary obstruction", section on 'Metal stents'.)

Preventing stent occlusion

Photodynamic therapy, RFA, and catheter-based brachytherapy — For most patients with extrahepatic cholangiocarcinoma and obstructive jaundice, we do not routinely add any form of local ablation therapy to stenting to improve stent patency. Our approach focuses on treatment of the tumor, and stent exchange/replacement as needed. We use local ablation selectively for tumor ingrowth causing recurrent stent occlusion, and in these cases, brachytherapy is preferred.

A major problem with biliary drainage using stents is stent reocclusion. In order to prolong stent patency, several strategies have been evaluated including ablating the tumor prior to stent placement using radiofrequency ablation (RFA), PDT after stent placement, and catheter-based brachytherapy with or without external beam radiation therapy (EBRT).

Photodynamic therapy – PDT involves the injection of an intravenous porphyrin photosensitizer followed by the endoscopic application of light (of a specific wavelength) to the tumor bed. The interaction between the light and the photoagent causes tumor cell death, presumably by the generation of oxygen free radicals.

Although PDT is not available at most institutions, experience with this technique in patients with cholangiocarcinoma is accumulating:

Early uncontrolled series suggested that, in addition to facilitating biliary decompression after stenting in patients with locally advanced disease, survival might be improved and stent occlusion rates lower, in patients who underwent PDT [17-24]. As an example, in one study of 143 patients, 72 treated with PDT, and 71 with stenting alone, the PDT group had modestly longer median survival (9.8 versus 7.3 months), and longer metal stent patency (median 215 versus 181 days, p = 0.018) [24].

A meta-analysis of eight trials (642 subjects) comparing PDT plus a stent versus a stent only (seven trials, including the two small randomized trials [25,26] and five other uncontrolled comparisons) or other treatment modalities for cholangiocarcinoma came to the following conclusions [27]:

-Overall survival was significantly better in patients who received PDT compared with in those who did not (hazard ratio [HR] 0.49, 95% CI 0.33-0.73).

-Of the five trials that assessed other indications for improvement, patients receiving PDT had improved biliary drainage and better quality of life. Stent reocclusion rates and duration of stent patency were not addressed.

-The main adverse events were cholangitis (37 versus 35 percent of those undergoing PDT and stenting only, respectively); and phototoxic reactions (11 percent in the PDT group). Liver abscess developed in five of the PDT-treated patients versus none in the stent only group, and hemorrhage occurred in four in the PDT group versus none in the stent only group.

-The quality of the evidence was low.

Radiofrequency ablation – RFA has been evaluated for prolonging the patency of biliary stenting for malignant biliary obstruction; most of the studies have combined analysis of patients with biliary obstruction from pancreatic or biliary malignancies; some studies apply the RFA endoscopically while others have applied it percutaneously. The following data are available:

A single published trial included 65 patients with malignant biliary obstruction from extrahepatic cholangiocarcinoma who were randomly assigned to RFA combined with biliary stenting or stenting alone [28]. At a median follow-up of 21 months, the RFA group had a significantly longer mean survival time (13.2 versus 8.3 months, p <0.01), and a longer mean duration of stent patency (6.8 versus 3.4 months, p = 0.02).

A systematic review of nine retrospective reports with a total of 505 patients came to the following conclusions [29]:

-The pooled weighted mean difference in stent patency was 50.6 days (95% CI 32.83-68.48), favoring RFA;

-Pooled survival analysis also showed improved survival in the RFA group (HR 1.395, 95% CI 1.145-1.7);

-There was a higher risk of postprocedure abdominal pain with RFA (31 versus 20 percent), but no significant difference with regard to risk of cholangitis, acute cholecystitis, pancreatitis, or hemobilia.

Outcomes from RFA (endoscopic or percutaneously applied) were compared with PDT in a systematic review and meta-analysis of 55 studies with a total of 2146 patients; most were retrospective or prospective single institution series, none directly compared RFA versus PDT [30]. A total of 1149 patients underwent treatment with PDT (33 studies), 545 had RFA (22 studies), and of all of the included studies 452 patients had treatment with a stent alone. The following conclusions were drawn:

-The pooled time of stent patency with PDT, RFA, and stent only treatment was 6.1 (95% CI 4.2-8), 5.5 (95% CI 4.2-6.7), and 4.7 (95% CI 2.6-6.7) months, respectively.

-The pooled survival rate with PDT, RFA, and the stent only treatment was 11.9 (95% CI 10.7-13.3), 8.1 (95% CI 6.4-9.9), and 6.7 (95% CI 4.9-8.4) months, respectively.

-The pooled rate of 30-day mortality with PDT, RFA, and stent only placement was 3.3 (95% CI 1.6-6.7), 7 (95% CI 4.1-11.7), and 4.9 (95% CI 1.7-13.1) percent, respectively.

-The pooled rates of cholangitis and liver abscess were highest among patients undergoing PDT (23.4 [95% CI 17.1-31.3] and 4.9 [95% CI 3.5-6.8] percent, respectively); among those undergoing RFA they were 9.5 (95% CI 5.4-15.9) and 2.6 (95% CI 1.5-4.5) percent, respectively.

Intraluminal brachytherapy – Brachytherapy is a form of RT in which a radiation source is placed inside or next to the area requiring treatment (eg, within the lumen of a biliary stent). Because the radiation emitted is generally active over only a relatively short distance, high doses of radiation can be delivered to the tumor while reducing the dose to the surrounding normal tissues. Brachytherapy can be delivered with either a low dose rate (LDR) or high dose rate (HDR) system. The International Commission on Radiation Units defines LDR brachytherapy as 0.4 to 2 Gy per hour, whereas HDR brachytherapy is delivered at >12 Gy per hour. (See "Radiation therapy techniques in cancer treatment", section on 'Brachytherapy'.)

The following data are available regarding intraluminal brachytherapy (ILBT) to prolong stent patency in patients with malignant biliary obstruction from an extrahepatic cholangiocarcinoma:

A systematic review and meta-analysis of 17 studies (one prospective randomized trial, two prospective phase I/II trials, 6 prospective cohort series, and 8 retrospective reports of HDR ILBT with or without EBRT) concluded that the duration of stent patency was longer with ILBT (three studies, 102 patients, median 10 versus 4 to 6 months; mean difference 4.68 months, 95% CI 2.43-6.9) [31]. Overall survival was also better with ILBT (four studies, 112 patients, mean difference 3.48 months, 95% CI 1.42-5.53). The data were more limited for other endpoints, but there was a trend toward prolonged local control and higher objective response rates with ILBT compared with stenting alone or in combination with EBRT. Radiation-related complications were reported in six studies, with duodenal ulcer being the most common; duodenal stenosis was the most common late toxicity. The timing and type of stents varied across studies, and there was heterogeneity on the anticancer treatment regimen, especially with regard to systemic or hepatic intra-arterial infusion chemotherapy, palliative resection, and transarterial chemoembolization. These issues limit the confidence in the conclusions of the analysis.

In a separate meta-analysis of 12 studies examining the benefit of LDR ILBT in patients with malignant obstructive jaundice (five small randomized trials all conducted in China, the remainder retrospective series), ILBT was associated with a significantly lower risk of stent reocclusion compared with stenting alone (11 studies, 615 patients, odds ratio 0.19, 95% CI 0.13-0.28), and a better mean survival (mean difference 3.15 months, 95% CI 2.64-3.66, p = <0.00001) [32]. Outcomes were comparable in terms of complications, but other oncologic outcomes (including local recurrence risk) were not reported.

Prophylactic antibiotics — Clinical practice with regard to prophylactic antibiotics is variable. Some clinicians, including some of the authors and editors associated with this topic review, routinely use prophylactic antibiotics, mainly to reduce rates of cholangitis, in patients receiving an endoscopically placed plastic or metal stent for long-term palliation of obstructive jaundice following a first episode of cholangitis. However, others do not continue prophylactic antibiotics following an episode of cholangitis as long as obstruction of the infected bile duct has been relieved with stent exchange, clearing of the indwelling stent, or placement of a second stent.

Prophylactic antibiotics have been examined as a means of reducing rates of stent occlusion and cholangitis among patients with indwelling stents. Two early trials and a pooled analysis of both failed to demonstrate any advantage in terms of stent occlusion, and they are not recommended for all patients who have an indwelling stent unless they are at risk for incomplete drainage. This topic is discussed elsewhere. (See "Infectious adverse events related to endoscopic retrograde cholangiopancreatography (ERCP)", section on 'Acute cholangitis'.)

However, some benefit in terms of lower rates of cholangitis was suggested in an early trial in which 94 patients with a plastic stent for palliation of malignant jaundice (mainly due to pancreatic cancer) were randomly assigned to ciprofloxacin (500 mg twice daily) or placebo [33]. Although there was no significant difference in long-term patency (as was seen in the other trials), patients who received prophylactic ciprofloxacin had significantly fewer episodes of cholangitis (23 versus 42 percent) and had better quality of life.

ANTINEOPLASTIC THERAPY

Overview of the therapeutic approach — For both intrahepatic and extrahepatic cholangiocarcinomas, complete surgical resection is a prerequisite for cure. A margin-negative resection offers the best chance of long-term survival [34], but this is often not possible given the central location of many of these tumors. (See "Surgical resection of localized cholangiocarcinoma".)

The optimal approach to the patient with locally advanced, unresectable cholangiocarcinoma depends on the clinical presentation and whether or not the tumor has been resected; our approach is outlined in the algorithm (algorithm 1) and discussed in the following sections.

Unresected patients

Biopsy — For locally advanced, unresectable intrahepatic and extrahepatic cholangiocarcinomas, a biopsy is warranted, both for confirmation of the diagnosis and for testing for molecular alterations that may indicate the potential for benefit from targeted therapies such as pembrolizumab (for deficient mismatch repair [dMMR] or high levels of microsatellite instability [MSI-H]) or a tropomyosin receptor kinase (TRK) inhibitor (for TRK fusion-positive tumors). (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors" and "TRK fusion-positive cancers and TRK inhibitor therapy".)

Systemic chemotherapy — For most patients with locally unresectable cholangiocarcinoma (either intrahepatic or extrahepatic), we suggest initial systemic chemotherapy rather than some form of locoregional therapy. One reason to start with chemotherapy is to allow the natural history of the disease to become manifest before embarking on locoregional therapy. Several chemotherapy regimens are active for treatment of advanced cholangiocarcinoma. We generally prefer gemcitabine plus cisplatin, which in the ABC trial, was superior to gemcitabine alone in patients with advanced disease [35]. Where available, S-1 plus gemcitabine is another option [36]. Another option for extrahepatic cholangiocarcinoma is capecitabine plus gemcitabine, as was used in the adjuvant Southwest Oncology Group (SWOG) S0809 trial [37]. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Rationale for adjuvant therapy' and "Systemic therapy for advanced cholangiocarcinoma", section on 'Gemcitabine plus cisplatin'.)

For patients without distant disease progression following a period of initial systemic chemotherapy (typically three to four months), locoregional therapy options are outlined below.

Locoregional therapies

Mass lesion in the liver — For most patients, we suggest the use of fluorouracil (FU)-based chemoradiotherapy rather than systemic chemotherapy alone. We suggest radiation dose escalation, using conformal treatment planning, to a biologic equivalent dose (BED) >80.5 Gy given with concurrent chemotherapy rather than conventional-fractionation radiation therapy (RT). Where available, stereotactic body radiation therapy (SBRT) may be an alternative option to dose-escalated RT. (See 'Radiation therapy and chemoradiotherapy' below.)

Another option, where local expertise is available, is hepatic arterial radioembolization using yttrium-90 (Y90) glass microspheres. If radioembolization is not available and the patient is not a candidate for chemoradiotherapy or SBRT, other options include local ablation (radiofrequency ablation [RFA] or microwave ablation), bland embolization, chemoembolization, or systemic chemotherapy alone. (See 'Local ablation, embolization, and hepatic intra-arterial chemotherapy' below.)

For patients with a locally advanced, unresectable, but nonmetastatic intrahepatic mass lesion, locoregional treatment may add benefit beyond that of systemic chemotherapy alone. This has been most convincingly shown in intrahepatic cholangiocarcinoma [38], but many of the studies exploring locoregional treatment in conjunction with systemic chemotherapy have included hilar tumors.

Radiation therapy and chemoradiotherapy — Approaches to RT for patients with presumed intrahepatic cholangiocarcinoma include external beam radiation therapy (EBRT) delivered either using conventional approaches with radiosensitizing doses of chemotherapy or using conformal treatment planning techniques (also with concurrent radiosensitizing doses of chemotherapy) and SBRT. SBRT is a form of EBRT that couples a high degree of anatomic targeting with high doses of radiation. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

There are no randomized trials directly comparing any of these approaches. In at least one retrospective review, patients treated with combined chemoradiotherapy using conventional-dose RT plus systemic chemotherapy had a better outcome (median progression-free survival 4.3 versus 1.9 months, overall survival 9.3 versus 6.3 months) than did those treated with systemic chemotherapy alone [39].

Higher dose RT approaches (ie, BED ≥80.5 Gy) that use three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or SBRT may be associated with better local control and, possibly, prolonged survival in patients with intrahepatic cholangiocarcinoma [40-49]. The benefit of higher dose RT can be illustrated by a series of 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma who were treated with definitive RT between 2002 and 2014 at doses ranging from 35 to 100 Gy in 3 to 30 fractions for a median BED of 80.5 Gy [42]. Seventy patients received systemic chemotherapy prior to RT, and the majority (63 percent) received concurrent chemotherapy with RT. At a median follow-up of 33 months, the three-year overall survival rate was 44 percent, and it was significantly higher for those receiving a BED >80.5 Gy (73 versus 38 percent); the corresponding local control rates were 78 versus 45 percent. These outcomes compare favorably with historical series that used conventional fractionation and doses of EBRT.

Technical advances over the last decade have created the ability to deliver more precise, highly conformal RT to a tumor, maximally sparing adjacent normal tissues. The enhanced capability to spare such normal tissues now permits the safe delivery of one to five fractions of high-dose RT to a target (ie, SBRT), whereas in the past, small fractions of daily RT over many weeks were typically used to spare normal tissues. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

Experience with SBRT for treatment of cholangiocarcinoma is limited, and most reports are single-institution, retrospective series involving limited numbers of both intrahepatic and hilar (Klatskin) cholangiocarcinomas. However, taken together, the reports demonstrate high rates of local control with modest toxicity. A meta-analysis of 11 of these reports (totaling 226 patients with either locally unresectable or recurrent cholangiocarcinoma) came to the following conclusions [50]:

The pooled one-year local control rate was 78.6 percent (95% CI 69.0-85.8), and the pooled one-year overall survival rate was 53.8 percent.

The most common toxicities were duodenal ulcer, gastric ulcer, and biliary toxicity, with an acute incidence of grade 3 or more of <10 percent each and a late incidence of 10 to 20 percent in most studies (although rates were much higher in one report [43]).

Some small series have demonstrated the safety of combining SBRT with systemic therapy. In one report of 10 patients with hilar cholangiocarcinoma treated with SBRT (30 Gy in three fractions) plus gemcitabine, local control was 80 percent, and the two-year survival rate was also 80 percent [47].

Importantly, no randomized trial has compared these newer RT techniques versus conventionally fractionated, fluoropyrimidine-based chemoradiotherapy. Furthermore, no trials have directly compared SBRT with other methods of radiation dose escalation or with conventional-fractionation chemoradiotherapy. One retrospective analysis of 170 patients with unresected intrahepatic cholangiocarcinoma derived from the National Cancer Database (NCDB) concluded that SBRT was associated with higher overall survival when compared with conventional-fractionation chemoradiotherapy or transarterial radioembolization [51], but the lack of random assignment or information about other forms of anticancer therapy renders this conclusion uninterpretable.

Proton beam irradiation represents another method of delivering high-dose chemoradiotherapy. Most data are limited to single-institution, retrospective studies. A prospective, multi-institutional phase II study evaluated the efficacy and safety of high-dose, hypofractionated proton beam therapy for unresectable hepatocellular (n = 44) and intrahepatic cholangiocarcinoma (n = 37). A dose of 67.5 Gy equivalent was delivered over 15 fractions. The two-year local control and overall survival rates were 94.1 and 46.5 percent, respectively, in the cholangiocarcinoma cohort [52].

Local ablation, embolization, and hepatic intra-arterial chemotherapy — For most patients, dose-escalated RT approaches are preferred over local methods of ablation, but radioembolization is a reasonable alternative to dose-escalated chemoradiotherapy or SBRT where local expertise is available.

For patients with unresectable intrahepatic cholangiocarcinoma, nonsurgical methods of tumor ablation that may provide adequate local palliation include RFA or microwave ablation [53], radioembolization using Y90-tagged glass or resin microspheres that are delivered selectively to the tumor via the hepatic artery [54-57], particle embolization with and without intra-arterial chemotherapy [54,55,58], and hepatic intra-arterial chemotherapy with or without systemic chemotherapy [54,59,60].

Hepatic arterial embolization therapy in particular seems to be a promising modality for localized tumors, and may convert some patients to potentially resectable disease [55,57,61-66].

The utility of first-line radioembolization with Y90 glass microspheres in conjunction with systemic chemotherapy was addressed in a multicenter phase II study of 41 patients with locally unresectable intrahepatic cholangiocarcinoma [57]. Chemotherapy consisted of eight cycles of cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 (reduced to 300 mg/m2 for the cycles immediately before and after radioembolization) on days 1 and 8 of each 21-day cycle. The radioembolization was administrated during cycle 1 for disease involving one lobe of the liver or during cycles 1 and 3 for bilobar disease. The objective response rate at three months was 41 percent, and 98 percent achieved disease control. Grade 3 or 4 toxic effects occurred in 29 patients (71 percent), predominantly neutropenia, thrombocytopenia, and abdominal pain. Notably, 75 percent of patients with cirrhosis experienced some form of liver failure, compared with 17 percent of those without cirrhosis, which was irreversible in a large portion of patients. Median overall survival was 22 months, with 75 and 45 percent still alive at 12 and 24 months, respectively. Nine patients (22 percent) could be downstaged to surgical intervention, with eight (20 percent of the total enrolled) achieving complete (R0) resection. A phase III trial is planned.

Whether results from any of these local ablative therapies are better than those that can be achieved using chemoradiotherapy or chemotherapy alone is unclear; randomized trials are not available.

Malignant stricture with or without jaundice — For most patients with locally advanced, unresectable, nonmetastatic extrahepatic cholangiocarcinoma presenting as a malignant stricture, we suggest treatment with fluoropyrimidine-based chemoradiotherapy using conventional-dose EBRT. Conformal treatment planning is preferred if it is available. Given the close proximity of the small bowel, dose-escalated RT or SBRT is not recommended. Another option is catheter-based brachytherapy plus EBRT. Methods for biliary decompression in patients with obstructive jaundice are described above. (See 'Patients with obstructive jaundice' above.)

For antineoplastic therapy of locally advanced, unresectable, nonmetastatic extrahepatic cholangiocarcinoma, conventional-dose chemoradiotherapy (with or without further systemic chemotherapy) may relieve pain and contribute to biliary decompression [41,67-79]. At one year, 60 to 75 percent of patients are free of locoregional disease progression, and median survival approximates 7 to 12 months [69,80]. However, local recurrence remains the first site of disease progression in 50 to 75 percent of cases.

For patients with obstructive jaundice, antineoplastic therapy should be integrated with local methods to palliate jaundice (especially endoscopically placed stents with or without photodynamic therapy [PDT]). (See 'Patients with obstructive jaundice' above.)

In general, we do not suggest escalating the radiation dose by using SBRT or dose-escalated conventional RT. One approach that could be considered is the addition of transcatheter brachytherapy to EBRT. With brachytherapy, thin wires of iridium-192 (Ir192) are introduced into the bile ducts via a catheter; these deliver high-dose RT to the tumor but very low doses to surrounding tissue [81-83]. Randomized trials comparing this approach with RT alone or with other methods of radiation dose escalation are not available.

Reassessment for resectability — Most patients undergoing combined treatment with chemotherapy and either radioembolization or concurrent chemoradiotherapy for locally advanced, unresectable intrahepatic cholangiocarcinomas that have not yet been resected will be treated with the goal of palliation; however, select patients will have a sufficient response to neoadjuvant treatment to permit later resection [57,84-86]. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Neoadjuvant approaches'.)

Role of liver transplantation — Some centers consider orthotopic liver transplantation (OLT) or living donor liver transplantation to represent a standard therapy for highly selected patients with cholangiocarcinoma. Indeed, updated consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) state that referral to a transplant center should be "considered" for patients with locally advanced, unresectable extrahepatic cholangiocarcinoma [87]. (See 'Guidelines from expert groups' below.)

However, in our view, given the poor sensitivity of noninvasive staging and the issues with donor allocation, liver transplantation should only be carried out for highly selected patients (eg, those with hilar cholangiocarcinoma in the setting of primary sclerosing cholangitis) after careful consideration at experienced centers and only in the context of a clinical trial.

Liver transplantation has been evaluated as a treatment for both intrahepatic and hilar cholangiocarcinoma, with mixed results. In many cases, the patients were transplanted for primary sclerosing cholangitis, and they were found to have incidental cholangiocarcinoma in their native liver. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Prior to orthotopic liver transplantation' and "Primary sclerosing cholangitis in adults: Management".)

Interest in liver transplantation as a treatment for cholangiocarcinoma has been revived by the published experience of the Mayo Clinic, which reported a five-year survival rate of 82 percent in a series of 38 patients with initially unresectable hilar cholangiocarcinoma arising in the setting of primary sclerosing cholangitis who were treated with preoperative chemoradiotherapy followed by exploratory laparotomy, to exclude metastatic disease, and underwent liver transplant [88]. A more recent multicenter report using this protocol showed a 53 percent five-year survival using an intent-to-treat analysis. In addition, the posttransplant recurrence-free survival was 65 percent at five years [89]. It should be noted that these patients were highly selected and that only rarely would a locally advanced cholangiocarcinoma patient be eligible for liver transplantation. These protocols also do not include patients with intrahepatic cholangiocarcinoma. This subject is addressed in detail separately. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Prior to orthotopic liver transplantation'.)

Prior surgery

Intrahepatic cholangiocarcinoma

Microscopically positive margins — For most patients who have undergone resection and have microscopically positive margins (R1 resection), we suggest the use of systemic chemotherapy plus FU-based chemoradiotherapy using conventional-fractionation RT (54 to 59.4 Gy). Options for systemic chemotherapy in this setting are addressed elsewhere. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Choice of regimen'.)

Despite uncertainty as to its survival benefit, postoperative adjuvant therapy (chemoradiotherapy using conventional-dose RT, systemic chemotherapy, or a combination approach) is widely recommended by expert groups, including the NCCN [87], for patients with microscopic residual disease following resection of intrahepatic cholangiocarcinoma. This subject is addressed separately. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Adjuvant therapy' and "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Guidelines from expert groups'.)

Macroscopically positive margins — For extensive residual local disease (ie, R2 resection) in a patient who is a candidate for chemoradiotherapy (no evidence of distant metastatic disease, able to tolerate chemoradiotherapy), we suggest systemic chemotherapy followed by either FU-based chemoradiotherapy with dose escalation to a BED >80.5 Gy or SBRT rather than conventional-fractionation chemoradiotherapy. If the patient is not a candidate for chemoradiotherapy, options include local ablation, hepatic arterial embolization, or systemic chemotherapy alone. (See 'Radiation therapy and chemoradiotherapy' above.)

Extrahepatic cholangiocarcinoma

Microscopically positive margins — For most patients who have undergone resection of extrahepatic cholangiocarcinoma and have either microscopically or macroscopically positive margins (ie, R1 or R2 resection), we suggest the use of systemic chemotherapy plus FU-based chemoradiotherapy using conventional-fractionation RT (54 to 59.4 Gy). Options for systemic chemotherapy in this setting are addressed elsewhere. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Choice of regimen'.)

Despite uncertainty as to its survival benefit, postoperative adjuvant therapy (chemoradiotherapy using conventional-dose RT, systemic chemotherapy, or a combination approach) is widely recommended by expert groups, including the NCCN [87], for patients with microscopic residual disease following resection of extrahepatic cholangiocarcinoma. This subject is addressed separately. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Adjuvant therapy'.)

Macroscopically positive margins — Our approach to patients with macroscopic residual disease after resection of extrahepatic cholangiocarcinoma parallels that for patients with locally advanced, initially unresectable tumors. For most patients, we suggest chemotherapy plus chemoradiotherapy using conventional-fractionation RT. In general, we do not suggest escalating the radiation dose by using SBRT or dose-escalated conventional RT. Another option is systemic chemotherapy alone using cisplatin plus gemcitabine, a fluoropyrimidine plus gemcitabine, or a single-agent fluoropyrimidine. (See 'Malignant stricture with or without jaundice' above.)

Guidelines from expert groups — Consensus-based guidelines are available from two expert groups: the NCCN [87] and the European Society of Medical Oncology (ESMO) [90].

National Comprehensive Cancer Network — Updated guidelines from the NCCN on treatment of patients with unresectable cholangiocarcinoma suggest the following [87]:

Intrahepatic cholangiocarcinoma

For patients with locally advanced, unresectable disease, options include gemcitabine/cisplatin combination chemotherapy, a clinical trial, a fluoropyrimidine-based or gemcitabine-based chemotherapy regimen, EBRT with concurrent fluoropyrimidine or locoregional therapy (eg, RT or arterial-directed therapies), best supportive care, or targeted therapy (where appropriate, eg, pembrolizumab for MSI-H/dMMR tumors). (See 'Biopsy' above.)

For patients with resected, microscopically positive margins, options include fluoropyrimidine-based or gemcitabine-based chemotherapy, fluoropyrimidine-based chemoradiotherapy, fluoropyrimidine-based or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiotherapy, fluoropyrimidine-based chemoradiotherapy followed by fluoropyrimidine-based or gemcitabine-based chemotherapy, or a clinical trial. For extensive residual local disease (R2 resection), options include gemcitabine/cisplatin combination chemotherapy, a clinical trial, fluoropyrimidine-based or gemcitabine-based chemotherapy, EBRT with concurrent fluoropyrimidine or locoregional therapy (eg, RT or arterial-directed therapies), best supportive care, or targeted therapies (where appropriate).

Extrahepatic cholangiocarcinoma

For patients with locally advanced, unresectable disease, they suggest "considering" referral to a transplant program. Options for primary treatment include gemcitabine/cisplatin combination chemotherapy, a clinical trial, a fluoropyrimidine-based or gemcitabine-based chemotherapy regimen, EBRT with concurrent fluoropyrimidine therapy or RT, targeted therapy (where appropriate), or best supportive care.

For patients with positive margins (microscopic or macroscopic), they suggest fluoropyrimidine-based or gemcitabine-based chemotherapy, fluoropyrimidine-based chemoradiotherapy, fluoropyrimidine-based or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiotherapy, fluoropyrimidine-based chemoradiotherapy followed by fluoropyrimidine-based or gemcitabine-based chemotherapy, or a clinical trial.

European Society of Medical Oncology — Guidelines from ESMO include the following [90]:

For postoperative treatment after noncurative resection of intrahepatic or extrahepatic cholangiocarcinoma, no specific recommendation is made. The guidelines state only that, following surgery, adjuvant therapy (RT, chemoradiotherapy, or chemotherapy alone) may be offered to patients with the understanding that the evidence base is weak and only after a risk-benefit assessment; participation in clinical trials should be encouraged.

For locally advanced, unresectable cholangiocarcinoma, systemic chemotherapy is the treatment of choice; RT may be considered in patients with localized disease after first-line chemotherapy. Patients should be encouraged to participate in a clinical trial. Neoadjuvant therapy and liver transplantation should not be offered outside of the scope of a clinical trial.

SUMMARY AND RECOMMENDATIONS

Definition – Locally advanced cholangiocarcinoma encompasses a heterogeneous mix of patients who fit the following categories (see 'Introduction' above):

Locally advanced, unresectable, nonmetastatic disease, which may present as an isolated intrahepatic mass with imaging characteristics consistent with malignancy but not hepatocellular cancer, or an apparent mass lesion with a malignant biliary stricture, often with jaundice. (See "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma", section on 'Preoperative assessment and criteria for resectability'.)

Microscopic or macroscopic residual disease following resection of either an intrahepatic or an extrahepatic cholangiocarcinoma.

Patients with obstructive jaundice

Palliation of jaundice can be accomplished with operative biliary-enteric bypass or with endoscopic/percutaneous stenting of the biliary tree. For most patients, nonoperative management is preferred. (See 'Patients with obstructive jaundice' above.)

Specific recommendations for the type of stent, and the method of placement are provided separately. (See "Endoscopic stenting for malignant biliary obstruction".)

For most patients with an indwelling biliary stent, prophylactic antibiotics are not warranted unless they are at risk for incomplete drainage. Some clinicians routinely prescribe prophylactic antibiotics in patients receiving an endoscopically placed plastic or metal stent for long-term palliation of obstructive jaundice after the first episode of cholangitis to reduce rates of recurrent cholangitis, but practice is variable. (See 'Prophylactic antibiotics' above.)

For most patients with extrahepatic cholangiocarcinoma and obstructive jaundice, we do not routinely add any form of local ablation therapy to stenting to improve stent patency. Our approach focuses on treatment of the tumor, and stent exchange/replacement as needed. We use local ablation selectively for tumor ingrowth causing recurrent stent occlusion, and in these cases, brachytherapy is preferred. (See 'Photodynamic therapy, RFA, and catheter-based brachytherapy' above.)

Antineoplastic therapy – The following represents our general approach to treatment, which is also outlined in the algorithm (algorithm 1):

Unresected tumor:

-For most patients with locally unresectable intrahepatic or extrahepatic cholangiocarcinoma we suggest initial systemic chemotherapy rather than locoregional therapy (Grade 2C). We generally prefer gemcitabine plus cisplatin (table 1). Other options include capecitabine plus gemcitabine (table 2), a fluoropyrimidine alone, or where available, S-1 plus gemcitabine. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'Gemcitabine plus cisplatin'.)

For patients without distant disease progression following a period of initial systemic chemotherapy (typically three to four months), locoregional therapy options are outlined below:

-For patients presenting with an unresectable intrahepatic mass lesion, we suggest fluorouracil (FU)-based chemoradiotherapy (CRT) rather than continued systemic chemotherapy (Grade 2C). During CRT, we suggest radiation dose escalation using conformal treatment planning to a biologic equivalent dose (BED) >80.5 Gy rather than conventional-fractionation RT (Grade 2C). Where available, stereotactic body radiation therapy (SBRT) is an alternative to dose-escalated RT. (See 'Radiation therapy and chemoradiotherapy' above.)

Another option, where local expertise is available, is systemic chemotherapy plus transarterial radioembolization (TARE). If TARE is not available and the patient is not a candidate for CRT or SBRT, other options include local ablation (radiofrequency or microwave), bland embolization, chemoembolization, or systemic chemotherapy alone. (See 'Local ablation, embolization, and hepatic intra-arterial chemotherapy' above.)

-For most patients presenting with a malignant stricture, we suggest fluoropyrimidine-based CRT using conventional-dose external beam RT (EBRT) (Grade 2C). Given the close proximity of the small bowel, dose-escalated RT or SBRT is not recommended. Another option is catheter-based brachytherapy plus EBRT. (See 'Malignant stricture with or without jaundice' above.)

-Reassessment for resection after treatment is reasonable in the absence of distant metastases. (See 'Reassessment for resectability' above.)

-Referral to a transplant center is reasonable for patients with unresectable extrahepatic cholangiocarcinoma who are suitable candidates for liver transplantation. However, liver transplantation should only be carried out for highly selected patients after careful consideration at experienced centers and only in the context of a clinical trial. (See 'Role of liver transplantation' above.)

Resected tumor with positive margins:

-Intrahepatic – For intrahepatic tumors with microscopically positive margins (R1 resection), we suggest postoperative chemotherapy followed by conventional-dose fractionated CRT (Grade 2C). (See 'Microscopically positive margins' above.)

For extensive residual local disease (R2 resection) in a patient with no evidence of distant metastases we suggest systemic chemotherapy followed by either FU-based CRT with dose escalation to a BED >80.5 Gy or SBRT, rather than conventional-fractionation CRT (Grade 2C). If the patient is not a candidate for CRT or SBRT, options include local ablation, hepatic arterial embolization, or systemic chemotherapy alone. (See 'Macroscopically positive margins' above.)

-Extrahepatic – For extrahepatic tumors with either R1 or R2 resection, we suggest chemotherapy followed by conventional-fractionation FU-based CRT (Grade 2C). For patients with extensive residual disease, if the patient is not a candidate for CRT, systemic chemotherapy alone is a reasonable option. (See 'Extrahepatic cholangiocarcinoma' above.)

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References

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