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Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma

Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma
Literature review current through: May 2024.
This topic last updated: Jan 31, 2024.

INTRODUCTION — Cholangiocarcinomas are rare malignancies arising from the epithelial cells of the intrahepatic and extrahepatic bile ducts. Surgery provides the only possibility for cure, but only a minority of patients who present with early stage disease are candidates for resection. Distal cholangiocarcinomas (figure 1) have the highest resectability rates while proximal (both intrahepatic and perihilar) tumors have the lowest. Resectability rates for cholangiocarcinomas have increased over time, due in part to more aggressive operative strategies and broadened criteria for resectability. However, the majority of cases still recur despite complete surgical resection. (See "Surgical resection of localized cholangiocarcinoma".)

Following complete surgical resection, relapse patterns are both local and distant metastases (typically hepatic or peritoneal recurrence). These data provide the rationale for exploring adjuvant systemic chemotherapy as well as radiotherapy-based regimens after resection. (See 'Rationale for adjuvant therapy' below.)

Adjuvant and neoadjuvant treatments for cholangiocarcinoma and prognosis for patients with localized, potentially resectable disease will be reviewed here. Epidemiology, pathology, classification, staging, clinical presentation, and diagnosis, as well as surgical management of localized disease, treatment for locally advanced disease, and systemic therapy for metastatic disease are discussed elsewhere. (See "Clinical manifestations and diagnosis of cholangiocarcinoma" and "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma" and "Surgical resection of localized cholangiocarcinoma" and "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma" and "Systemic therapy for advanced cholangiocarcinoma".)

PREOPERATIVE ASSESSMENT AND CRITERIA FOR RESECTABILITY — Imaging is used to diagnose and accurately stage the tumor and may include contrast-enhanced multidetector row computed tomography (MDCT) of the abdomen, cholangiopancreatography (magnetic resonance, endoscopic, transhepatic), and possibly fluorodeoxyglucose-positron emission tomography. (See "Clinical manifestations and diagnosis of cholangiocarcinoma", section on 'The staging workup'.)

The traditional guidelines for resectability of cholangiocarcinoma in the United States include:

Absence of retropancreatic and paraceliac nodal metastases or distant liver metastases

Absence of invasion of the portal vein or main hepatic artery (although some centers support en bloc resection with vascular reconstruction in such cases)

Absence of extrahepatic adjacent organ invasion

Absence of disseminated disease

Additional criteria are specific to tumor location. As an example, radiographic criteria that suggest local unresectability of perihilar tumors include bilateral hepatic duct involvement up to secondary radicles bilaterally, encasement or occlusion of the main portal vein proximal to its bifurcation, atrophy of one liver lobe with encasement of the contralateral portal vein branch, atrophy of one liver lobe with contralateral secondary biliary radicle involvement, or involvement of bilateral hepatic arteries. However, as a general rule, true resectability is ultimately determined at surgery, particularly with perihilar tumors. Due to their location within the upper hepatoduodenal ligament, these tumors often extend into the liver and major vascular structures, and preoperative evaluation of resectability is often difficult. Thus, surgical exploration is the appropriate treatment for potentially resectable proximal bile duct carcinomas whenever feasible. (See "Surgical resection of localized cholangiocarcinoma", section on 'Criteria for resectability' and "Surgical resection of localized cholangiocarcinoma", section on 'Preoperative assessment'.)

Whether preoperative biliary decompression should be performed in patients with distal cholangiocarcinoma who present with obstructive jaundice is controversial. For more proximal tumors that will require liver resection, drainage of the future liver remnant is widely accepted. The best method (endoscopic versus percutaneous transhepatic) by which to perform preoperative biliary drainage is also debated. Issues related to preoperative biliary decompression and the use of portal vein embolization to increase the limits of safe resection are addressed elsewhere. (See "Surgical resection of localized cholangiocarcinoma", section on 'Preoperative biliary decompression' and "Surgical resection of localized cholangiocarcinoma", section on 'Preoperative portal vein embolization'.)

OVERVIEW OF SURGICAL TREATMENT AND PROGNOSIS

Prognostic factors — Among patients who undergo potentially curative resection for cholangiocarcinoma, long-term outcomes vary according to location and stage of the primary lesion, extent of surgery, associated comorbidities, and treatment-related complications [1-16]. The main prognostic factors are histologic margin status and lymph node involvement [5,17-19]:

In a retrospective review of 137 cases of resected extrahepatic cholangiocarcinoma, five-year survival rates for those with node-negative versus node-positive disease were 38 versus less than 10 percent, respectively [17].

The number of involved lymph nodes also influences outcomes. In a study of 320 patients undergoing resection of a perihilar cholangiocarcinoma, survival for patients with multiple nodal metastases was significantly worse than for those with a single metastasis (12 versus 28 percent at five years) [20].

Five-year survival rates are substantially better with clear as opposed to histologically involved margins (19 to 47 percent versus 0 to 12 percent, respectively) [13,14,21-26]. The most encouraging results (particularly with perihilar cholangiocarcinomas) come from reports that utilize expanded resection criteria and more extensive surgical procedures which increase the likelihood of negative resection margins. (See 'Perihilar cholangiocarcinoma' below and "Surgical resection of localized cholangiocarcinoma", section on 'Perihilar cholangiocarcinoma'.)

The prognostic impact of positive resection margins for intrahepatic cholangiocarcinomas is less certain [27-33]. Nevertheless, resection should not be attempted in a patient who is thought not to have completely resectable disease based upon staging studies.

For resected intrahepatic cholangiocarcinomas, lymph node metastases and hepatic venous invasion are also negative prognostic factors; the independent contribution of lymphovascular and perineural invasion is unclear [26,34,35]. (See 'Intrahepatic cholangiocarcinoma' below.)

For distal and intrahepatic cholangiocarcinomas, elevated preoperative values of the tumor marker CA 19-9 are also associated with inferior prognosis [36,37].

Newer data emphasize the adverse prognostic influence of certain molecular features such as TP53 and G12 RAS variants, especially the G12V allele, in intrahepatic cholangiocarcinomas [38,39].

Finally, outcomes are particularly poor for patients who develop perihilar or intrahepatic cholangiocarcinoma in the setting of primary sclerosing cholangitis [40,41]. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Cholangiocarcinoma' and "Primary sclerosing cholangitis in adults: Management", section on 'Gallbladder carcinoma and cholangiocarcinoma'.)

Distal cholangiocarcinoma — Distal lesions are usually treated with pancreaticoduodenectomy (Whipple procedure). A pylorus-preserving operation is preferable and is feasible in most patients. (See "Surgical resection of localized cholangiocarcinoma", section on 'Distal cholangiocarcinoma'.)

Lymph node involvement and depth of tumor invasion are important prognostic indicators, as reflected in the tumor, node, metastasis (TNM) staging criteria of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) [42-45]. Five-year survival rates range from 20 to 50 percent [1,5,46-51], but are as high as 54 to 62 percent in selected patients who undergo complete resection of a node-negative tumor [5,49]. For patients with lymph node-positive disease, five-year survival rates are under 20 percent [5,49,51].

The newest version (eighth edition, 2017) of the AJCC/UICC staging criteria for distal bile duct cancer is outlined in the table (table 1) [45]. Stratification of survival according to the 2017 T stage designations (which compared with earlier versions, are based upon the measured depth of invasion, in millimeters) is provided in the figure (figure 2) [42,45], while stratified survival according to the new N categories (which are expanded to N1 [one to three positive nodes] and N2 [four or more positive nodes]) is depicted in this figure (figure 3) [45].

However, cure rates may not actually be as high as some of these reports suggest since not all series distinguished distal cholangiocarcinoma from carcinoma of the ampulla of Vater, a disease that has a significantly higher cure rate. Both diseases (as well as some cases of pancreatic cancer) are often analyzed together as "periampullary" tumors. (See "Ampullary carcinoma: Epidemiology, clinical manifestations, diagnosis and staging".)

Intrahepatic cholangiocarcinoma — Intrahepatic cholangiocarcinoma is usually treated by hepatic resection to achieve negative resection margins. While it is clear that lymph node involvement is an important prognostic factor, lymphadenectomy does not appear to provide proven therapeutic benefit, and there is a lack of consensus as to whether or not it should be routinely performed [29,35,52-54]. However, grossly positive porta hepatis lymph nodes portend a very poor prognosis, and resection should only be offered in highly selected cases [29]. (See 'Prognostic factors' above and "Surgical resection of localized cholangiocarcinoma", section on 'Intrahepatic cholangiocarcinoma'.)

Outcomes depend upon disease stage (particularly the status of the lymph nodes and the presence of vascular invasion) and the ability to achieve negative margins [6-8,55,56].

The most recent version (eighth edition, 2017) of the AJCC/UICC staging criteria for intrahepatic bile duct cancer is outlined in the table (table 2) [57]. Survival stratified according to these T stage criteria (which compared with earlier versions, accounts for the prognostic effect of tumor size for T1 lesions by splitting this category into T1a and T1b, and for the equivalent prognostic value for vascular invasion and multifocality by combining T2a and T2b lesions into a single T2 category) is presented in the figure (figure 4) [57]. Survival stratified according to the prognostic stage groupings of the eighth edition in a separate multicenter series of 296 patients with intrahepatic cholangiocarcinoma, and compared with outcomes using the stage groupings of the 2010 seventh edition is outlined in the table (table 3) [58].

In order to further refine prognostic stratification, nomograms that incorporate tumor size, multiplicity, vascular invasion, nodal involvement, as well as preoperative serum tumor marker levels have been developed to predict survival following resection of an intrahepatic cholangiocarcinoma [59,60]. One such nomogram is depicted in the figure (figure 5) [59].

Five-year overall survival rates after surgical resection are in the range of 11 to 40 percent [61-64], but among patients undergoing complete (R0) resections for node-negative disease, five-year survival rates in single-institution series are as high as 44 to 63 percent [28,29,48,52,65-68]. Nevertheless, the majority of patients recur despite potentially curative (R0) resection.

The pattern of recurrence is unpredictable; although intrahepatic recurrences are observed most frequently and are present in most cases with multiple sites of recurrence, solitary extrahepatic recurrences can also be seen, particularly among patients with lymph node involvement [69,70]. In one contemporary large series of 920 patients undergoing curative intent resection for an intrahepatic cholangiocarcinoma, 607 recurred with a median follow-up of 38 months, with recurrences at the surgical margin in 24 percent, at a different intrahepatic site in 29 percent, at extrahepatic sites only in 15 percent, and both intra and extrahepatic sites in 32 percent [71].

At least some data suggest that outcomes have improved over time, but these apparent improvements may reflect better nonoperative therapy for unresectable disease [29,72], or better surgical patient selection through improved imaging techniques.

Perihilar cholangiocarcinoma — For perihilar cholangiocarcinomas, bile duct resection alone leads to high local recurrence rates due to early involvement of the confluence of the hepatic ducts (figure 1) and the caudate lobe branches. The addition of a modified hepatic resection has improved resectability rates, although potentially curative resections are still possible in fewer than one-half of patients, and the majority do not achieve long-term disease control [9,73-77].

Surgical treatment depends upon the Bismuth-Corlette classification (figure 6) (see "Surgical resection of localized cholangiocarcinoma", section on 'Perihilar cholangiocarcinoma'):

For type I and II lesions, the procedure is en bloc resection of the extrahepatic bile ducts and gallbladder with histologically clear margins and a regional lymphadenectomy with Roux-en-Y hepaticojejunostomy.

In addition to the above operations, type III tumors may require hepatic lobectomy.

Since type II and III lesions often involve the ducts of the caudate lobe, many surgeons recommend routine caudate lobectomy.

Type III and type IV tumors are amenable to potentially curative resection in centers with expertise in these procedures. However, type IV tumors are associated with a higher rate of positive surgical margins and significantly poorer five-year survival after resection than type I to III tumors [78]. Aggressive techniques, such as multiple hepatic segment resection with portal vein resection (hilar en bloc resection) to achieve negative margins, are routine in specialized centers.

Unfortunately, neither the Bismuth-Corlette classification nor the combined AJCC/UICC TNM stage (table 4) accurately assesses resectability, and true resectability may be ultimately determined only at surgery. (See 'Preoperative assessment and criteria for resectability' above and "Surgical resection of localized cholangiocarcinoma", section on 'Criteria for resectability'.)

Substantial progress has been made in curative resection for perihilar cholangiocarcinomas, at least some of which is attributed to the routine use of partial hepatectomy:

In selected series, five-year survival rates are between 20 and 50 percent, with the best results reported from Japan (table 5) [2,3,10,11,18,22,24,79-81].

The rate of margin-negative resections is consistently over 75 percent when partial hepatectomy (including resection of the caudate lobe) is added to the bile duct resection [2,3,18,24]. This aggressive approach has resulted in five-year survival rates that are 50 percent or better in some series [2,15,24,82]. However, these improvements have been accompanied by higher surgical mortality rates (7 to 10 versus 2 to 4 percent) in most [2,15,83,84], but not all series [24,82].

In addition, many clinicians suggest that the increasing use of postoperative chemoradiotherapy has contributed to the improved outcomes that have been seen in the last decade with hilar cholangiocarcinomas [24], although this has not been seen in all series [85], and the benefit of adjuvant therapy continues to be debated. (See 'Adjuvant therapy' below.)

The major prognostic factors are margin status, vascular invasion, and lymph node metastases, as reflected by the TNM staging criteria. The most recent version (eighth edition) of the AJCC/UICC staging criteria for intrahepatic bile duct cancer is outlined in the table (table 4) [57]. Survival stratified according to these most recent prognostic stage groupings is provided in the figure (figure 7) [86].

A nomogram to predict survival after resection of a perihilar cholangiocarcinoma that is based upon nodal involvement, tumor differentiation, and margin status has been proposed but not yet validated [87].

Other factors that are not captured by the staging criteria also influence outcome after resection. In one report of 65 patients undergoing resection for perihilar cholangiocarcinoma, variables that significantly affected survival included transmural extension to the gallbladder, histologic type (papillary better than adenosquamous), and gender (females better than males) [15]. Others suggest an adverse prognostic impact of a preoperative serum albumin level of less than 3 g/dL and total bilirubin above 10 mg/dL [21].

ADJUVANT THERAPY

Indications — All patients with resected cholangiocarcinoma should be encouraged to enroll in randomized trials testing various adjuvant therapy strategies. If a clinical trial is not available, or participation is not feasible, we suggest adjuvant therapy for all patients following resection, consistent with clinical practice guidelines from the American Society of Clinical Oncology (ASCO) [88]. (See 'Guidelines from expert groups' below.)

Choice of regimen — We suggest chemoradiotherapy (CRT) plus chemotherapy for patients with margin-positive or node-positive extrahepatic cholangiocarcinoma. For margin-positive intrahepatic cholangiocarcinoma, chemotherapy alone is a reasonable alternative for those who are not receiving CRT.

The choice of the specific regimen is empiric; there are few trials directly comparing gemcitabine-based versus fluoropyrimidine-based chemotherapy regimens, with or without concurrent CRT. In our view, acceptable options include the following:

Chemoradiotherapy:

Concurrent radiotherapy (RT) plus infusional FU (225 mg/m2 daily), as is widely used for other gastrointestinal tract malignancies, followed by an additional four months of chemotherapy with capecitabine alone (1000 mg/m2 twice daily for 14 of every 21 days).

Four cycles of capecitabine plus gemcitabine followed by concurrent RT plus oral capecitabine (1330 mg/m2 per day, divided into two daily doses), as was used in Southwest Oncology Group (SWOG) S0809 (table 6) [89].

Three weeks of gemcitabine alone followed by concurrent FU-based CRT and three additional months of gemcitabine monotherapy (table 7), as is used in the adjuvant setting for pancreatic cancer [90]. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Gemcitabine-based approaches'.)

Chemotherapy:

Capecitabine alone, as was used in the BILCAP trial [91], although we would at least start with a lower dose (no more than 1500 mg twice daily).

Single-agent gemcitabine, as was used in the European Study Group for Pancreatic Cancer (ESPAC)-3 trial (table 7) [92].

A preliminary report of the STAMP trial, presented at the 2022 ASCO annual meeting, concluded that adjuvant gemcitabine plus cisplatin had similar overall survival but markedly more toxicity as compared with capecitabine alone in patients with resected node-positive extrahepatic cholangiocarcinoma; we would not choose this regimen over capecitabine alone [93].

Leucovorin-modulated FU, as was also used in the ESPAC-3 trial [92].

Six months of S-1, as was used in JCOG1202, where available. (See 'Chemotherapy' below.)

Rationale for adjuvant therapy — Following complete surgical resection, the most common relapse pattern for distal and perihilar cholangiocarcinomas is local [82,94]. While distant metastases (typically a hepatic or peritoneal recurrence) are less common than as seen with gallbladder cancer, they are not rare, particularly with hilar cholangiocarcinomas. In one series, the initial recurrence involved a distant site in 41 percent of patients with a hilar cholangiocarcinoma (as compared with 85 percent of patients with gallbladder cancer) [94]. Others report that 60 percent of patients developed distant metastases following a microscopically complete (R0) resection for hilar cholangiocarcinoma [82].

On the other hand, surgical resection margins are often adequate for intrahepatic cholangiocarcinomas, and the recurrence pattern can be either intrahepatic, nodal, or extrahepatic distant recurrences (typically intraperitoneal) [28,95].

These data provide the rationale for exploring adjuvant systemic chemotherapy, as well as local RT-based regimens.

Meta-analysis – The benefits of adjuvant therapy following curative-intent surgery for biliary tract cancers (extrahepatic and intrahepatic bile duct as well as gallbladder cancer) were addressed in a meta-analysis that included a single randomized trial of chemotherapy alone (described above [96]), two Surveillance, Epidemiology, and End Results (SEER) registry analyses, and 17 retrospective institutional series, altogether totaling 6712 patients, of whom 1797 received some form of adjuvant therapy [97]. To be eligible, studies had to include patients who had curative-intent surgery alone (defined as R0 or microscopically positive [R1] margins) as a control group. There were eight studies of RT plus chemotherapy, three of chemotherapy alone, and nine of RT alone. Only one study (n = 11 patients) included intrahepatic cholangiocarcinoma.

The following results were noted:

Compared with surgery alone, the improvement in five-year survival with any adjuvant therapy was not statistically significant (pooled odds ratio [OR] for death 0.74, 95% CI 0.55-1.01). The results were similar when gallbladder and bile duct cancers were analyzed independently. However, the survival benefit from adjuvant therapy was statistically significant when data from the two large registry series (n = 1233 patients) were excluded (OR 0.53, 95% CI 0.39-0.72).

The benefits of adjuvant therapy were modality dependent. In a combined analysis of gallbladder and bile duct cancers, there was a significant survival benefit for chemotherapy (OR 0.39, 95% CI 0.23-0.66) and CRT (OR 0.61, 95% CI 0.38-0.99) but not RT alone (OR 0.98, 95% CI 0.67-1.43).

Patients with node-positive and margin-positive disease appeared to derive the clearest survival benefit from adjuvant therapy:

-Pooled data confirmed a statistically significant overall survival advantage for any adjuvant therapy in node-positive disease (OR 0.49, 95% CI 0.30-0.80). The majority of these patients (77 percent) had received chemotherapy alone, while the remainder underwent CRT.

-Similarly, a significant benefit for any adjuvant therapy was shown for patients with margin-positive disease (OR 0.36, 95% CI 0.19-0.68).

-Nearly two-thirds of the treated R1 patients (63 percent) had received RT alone as a component of adjuvant therapy, while the majority of R0 studies used CRT, and most included node-positive patients. Following R1 resection, there was a statistically significant benefit from adjuvant RT (OR 0.33, 95% CI 0.14-0.81), while after R0 resection, adjuvant RT alone was associated with a trend toward worse overall survival (OR 1.26, 95% CI 0.88-1.79). However, most of the patients with R0 disease were node positive and received a combination of chemotherapy and RT, so the comparison is not well matched.

There were only limited data to address the benefit of chemotherapy in patients with node-negative disease, limiting the conclusions that could be reached in this group.

While this analysis supports clinical practice (ie, adjuvant therapy for high-risk subgroups with bile duct cancer), it does not resolve the question as to the best treatment strategy for high-risk patients or adequately address the benefit of adjuvant therapy for patients with lower risk (ie, node-negative) disease. High-quality, sufficiently powered, randomized trials remain needed in this area, several of which are ongoing [98,99].

Benefit of individual strategies

Radiotherapy and chemoradiotherapy — Fluoropyrimidine-based CRT is often offered to patients with cholangiocarcinoma following a macroscopically incomplete (R2) resection. In this setting, its main benefit is thought to be in enhanced local control. CRT for locally advanced cholangiocarcinoma is discussed elsewhere. (See "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma".)

Among patients undergoing R0 or R1 resection for cholangiocarcinoma, the benefit of RT with or without chemotherapy is uncertain:

No high-quality prospective randomized trials are available that establish the benefit of adjuvant RT in patients with completely resected disease. One small randomized trial conducted in a mixed population of 207 patients with pancreatic or periampullary malignancies (75 to 80 percent margin negative) failed to demonstrate a survival benefit for postoperative fluoropyrimidine-based CRT compared with surgery alone [100]. However, there were fewer than 100 patients with periampullary cancers in this trial, only some of which were biliary cancers. Furthermore, 20 percent of the patients in the treatment arm received no adjuvant treatment because of postoperative complications or refusal.

Many (but not all [63,101-103]) retrospective series and small phase II studies (most of which consist of a heterogeneous mix of patients with completely and incompletely resected intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer) suggest superior outcomes for patients who received postoperative CRT compared with historical series of patients who did not undergo CRT; however, the interpretation of most of these results is limited by treatment selection bias [89,104-110]. As an example, in the SWOG-0809 study, in which 79 patients with extrahepatic cholangiocarcinoma or gallbladder cancer at high risk of recurrence (ie, T2-4, N+ or margin positive) all received four 21-day courses of gemcitabine plus capecitabine followed by capecitabine-based CRT (45 Gy to regional nodes and 54 to 59.4 Gy to the tumor bed), the observed two-year survival was 65 percent, and it was similar in R0 and R1-resected patients (67 and 60 percent, respectively), which compared favorably with historical controls, particularly for R1-resected patients [89].

One analysis attempted to control for relevant prognostic variables using a cohort of 6317 patients with surgically resected distal cholangiocarcinoma derived from the National Cancer Database from 2004 to 2016; a cohort of 1509 who received adjuvant RT was propensity matched to a cohort of 1509 who did not receive RT for both patient-related (including nodal classification, margin status, receipt of adjuvant chemotherapy) and hospital-related variables (including center volume and facility type) [109]. In the overall cohort, the five-year overall survival rate was 30 percent. In the matched cohort, patients receiving RT had a small but statistically significant survival advantage (five-year survival 28 versus 25 percent, p = 0.17).

Despite the paucity of evidence of benefit, a year 2019 Clinical Practice Guideline from ASCO suggests that CRT should be offered to patients with resected extrahepatic cholangiocarcinoma who have an R1 surgical margin [88], largely based on the phase II SWOG-0809 study. We suggest CRT in addition to chemotherapy for patients with either margin-positive or node-positive disease.

If CRT is chosen, the choice of regimen is empiric; there are no comparative trials of different regimens. The following regimens are all acceptable options:

Some centers prefer infusional FU (225 mg/m2 daily for five weeks) during RT, but increasingly, capecitabine (825 mg/m2 twice daily during the five weeks of RT) is used because of its convenience. The doses selected are extrapolated from the experience with capecitabine-based CRT in rectal cancer. (See "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy", section on 'Orally active fluoropyrimidines'.)

Others prefer four cycles of capecitabine plus gemcitabine followed by concurrent RT plus oral capecitabine (1330 mg/m2 per day, divided into two daily doses), as was used in SWOG S0809 (table 6) [89].

Three weeks of gemcitabine alone followed by concurrent FU-based CRT and three additional months of gemcitabine monotherapy (table 7), as is used in the adjuvant setting for pancreatic cancer [90]. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Gemcitabine-based approaches'.)

Chemotherapy — Although benefit has been suggested in retrospective reports [111-117], only one [118] of several randomized trials in patients with completely or incompletely resected cholangiocarcinoma have demonstrated a significant survival benefit for adjuvant chemotherapy; the rest have not [91,92,96,119,120]. As examples:

JCOG1202 – A randomized phase III trial conducted in Japan (JCOG1202; the ASCOT trial) demonstrated an overall survival (OS) benefit for adjuvant chemotherapy with S-1 over resection alone. In this study, 440 patients who had undergone at least a microscopically complete (R0/R1) resection for cancer of the gallbladder, ampulla of Vater, or intrahepatic or extrahepatic cholangiocarcinoma were randomly assigned to either adjuvant chemotherapy with 24 weeks of oral S-1 (40 mg/m2 twice daily for four weeks on, two weeks off) or observation [118].

At median follow-up of 46 months, compared with observation, adjuvant S-1 improved OS (three-year OS 77 versus 68 percent, HR 0.69, 95% CI 0.51-0.94) and had a nonstatistically significant trend toward longer relapse-free survival (RFS; three-year RFS 62 versus 51 percent, HR 0.80, 95% CI 0.61-1.04). S-1 was reasonably well-tolerated; the most common grade 3 or 4 adverse events were biliary tract infection in 7 percent; and diarrhea, anorexia, and fatigue in 3 percent each. (See "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation".)

Whether and how these results can be extrapolated to other populations is unclear. S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer; it is not available in the United States.

Negative trials – Other large trials in broader populations have failed to confirm a survival benefit [91,92,119,120]; the two largest are described in detail:

ESPAC-3 – In the international ESPAC-3 trial, 428 patients with periampullary malignancies (297 ampullary, 96 bile duct, 35 other) were randomly assigned to one of three arms: observation, six months of leucovorin-modulated FU, or six months of single-agent gemcitabine [92]. The use of adjuvant chemotherapy was associated with a potentially meaningful overall survival advantage, but it was not statistically significant (median 43 versus 35 months, hazard ratio [HR] 0.86, 95% CI 0.66-1.11). In a preplanned subset analysis of the 96 patients with bile duct cancer, the median survivals were 27, 18, and 20 months with observation, FU/leucovorin, and gemcitabine, respectively, and not significantly different. (See "Ampullary carcinoma: Treatment and prognosis", section on 'Chemotherapy alone'.)

BILCAP trial – In the phase III BILCAP trial, 447 patients with completely resected cholangiocarcinoma (84 intrahepatic, 128 hilar, 156 extrahepatic) or gallbladder cancer (n = 79) were randomly assigned to eight cycles of capecitabine (1250 mg/m2 twice daily on days 1 to 14 every 21 days) or placebo [91]. Overall, 207 (46 percent) had node-negative disease, and the margins were negative (R0 resection) in 279 (62 percent) and microscopically positive (R1 resection) in 168 (38 percent). There was a potentially clinically meaningful, although not statistically significant, improvement in overall survival according to the intent to treat analysis (median 51 versus 36 months, HR 0.81, 95% CI 0.63-1.04). The benefit was statistically significant when ineligible patients (four in each group) and the 10 patients who received no postoperative capecitabine doses despite being randomized to receive the drug were eliminated from the analysis (per protocol analysis, median overall survival 53 versus 36 months, HR 0.75, 95% CI 0.58-0.97).

The survival curves did not separate over time, and the results were similar in a later analysis with a median follow-up of 106 months [121].

We view these results as less than definitive given the heterogeneity of the enrolled patient population, the high rate of R1 resection, and the failure to achieve statistical significance. Furthermore, in our experience, a dose of 1250 mg/m2 twice daily is not well tolerated in American populations.

Meta-analyses – At least two meta-analyses have been conducted of these trials, both of which concluded that benefit for adjuvant chemotherapy could not be shown:

-A Cochrane review of four of these randomized trials [91,96,119,120] evaluating the benefit of adjuvant chemotherapy versus no chemotherapy for resectable cholangiocarcinoma concluded that the evidence was uncertain as to whether postoperative chemotherapy had any influence on all-cause mortality (RR 0.92, 95% CI 0.84-1.01; 4 trials 867 participants), or on serious adverse events (RR 17.82, 95% CI 2.43-130.82; 1 trial, 219 participants) [122]. They also noted that none of the trials reported data on health-related quality of life, cancer-related mortality, time to tumor recurrence, and nonserious adverse events. There was insufficient information to address the optimal chemotherapy regimen.

-A later individual patient data meta-analysis of the BCAT and PRODIGE 12 trials (gemcitabine with or without oxaliplatin versus observation) also concluded that there was no significant benefit for gemcitabine-based adjuvant chemotherapy for either relapse-free or overall survival [119,120].

Despite these results, a year 2019 Clinical Practice Guideline from ASCO suggested that patients with resected biliary tract cancer should be offered six months of adjuvant capecitabine alone, largely based on the BILCAP trial, and that CRT should be offered only to patients with resected extrahepatic cholangiocarcinoma who have an R1 surgical margin [88]. NCCN offers six months of capecitabine as the preferred regimen for adjuvant therapy for resected cholangiocarcinoma [123]. (See 'Guidelines from expert groups' below.)

However, we disagree with the ASCO conclusions, and continue to suggest CRT plus chemotherapy rather than chemotherapy alone for patients with completely resected, node-positive or margin-positive cholangiocarcinoma. For patients not receiving CRT, six months of postoperative chemotherapy alone is an option. If capecitabine is chosen, we would start treatment with no more than a 1500 mg total dose twice daily. Where available, six months of adjuvant S-1 is an appropriate alternative. (See 'Guidelines from expert groups' below.)

Hepatic artery-based therapies for intrahepatic cholangiocarcinoma — There is insufficient evidence for the use of any hepatic artery-based therapy after complete resection of an intrahepatic cholangiocarcinoma, and this approach cannot be routinely recommended, except in the context of a clinical trial.

The majority of the blood supply to an intrahepatic tumor is derived from the hepatic artery rather than the portal vein. This has led to the development of techniques designed to eliminate the tumor's blood supply by particle embolization and/or directly infuse cytotoxic chemotherapy into the branch of the hepatic artery that feeds the tumor (transarterial embolization or chemoembolization [TACE]). Another technique, transarterial radioembolization (TARE), is a method to deliver focal RT by delivering radioactive isotopes (eg, iodine-131 [131-I]-labeled lipiodol or yttrium-90 [90-Y]-tagged glass or resin microspheres) selectively to the tumor via the hepatic artery.

Interest in embolization has been prompted by experience, predominantly with TARE, in patients with locally advanced unresectable intrahepatic cholangiocarcinoma. (See "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma", section on 'Local ablation, embolization, and hepatic intra-arterial chemotherapy'.)

There are no randomized trials addressing the benefit for TACE in the adjuvant setting after resection of intrahepatic cholangiocarcinomas. A systematic review and meta-analysis of 11 retrospective studies addressing the value of TACE in intrahepatic cholangiocarcinoma included six reports comparing postsurgical prophylactic TACE versus "no TACE" [124]. The comparator group in the six reports was no other adjuvant therapy in two [125,126] and not explicitly stated in the remainder [127-130]. In subgroup analysis of the six studies, adjuvant TACE was associated with a significantly better overall median survival (six studies, 2046 patients, odds ratio [OR] for death 0.76, 95% CI 0.65-0.90), and better survival at one-year (OR for survival 1.91, 95% CI 1.30-2.62), three years (OR 1.58, 95% CI 1.17-2.15), and five years (OR 1.51, 95% CI 1.08-2.10). There was only a trend toward improved disease-free survival with postoperative TACE (HR 0.83, 95% CI 0.36-1.93). The retrospective nature of all of these studies and lack of a randomly assigned control group limit the interpretation of these data.

There are no published data on use of TARE on the adjuvant setting.

Guidelines from expert groups — Consensus-based guidelines for adjuvant therapy after resection of bile duct cancer are available from three expert groups; given the lack of definitive data, it is not surprising that they are less than definitive:

ASCO issued a Clinical Practice Guideline in 2019 suggesting that all patients with resected biliary tract cancer should be offered six months of chemotherapy with capecitabine, and that patients with extrahepatic cholangiocarcinoma and a positive surgical resection margin may be offered CRT [88]. A shared decision-making approach was recommended, balancing the risk of harm and the potential for benefit associated with RT. Notably, these conclusions were based on very limited evidence and only retrospective series evaluating the benefit of CRT, many of which suggested benefit limited to those with positive resection margins. (See 'Chemotherapy' above and 'Radiotherapy and chemoradiotherapy' above.)

The National Comprehensive Cancer Network (NCCN) suggests the following [123]:

Extrahepatic cholangiocarcinoma:

For patients with resected, margin-negative extrahepatic cholangiocarcinoma with negative regional nodes, observation, fluoropyrimidine or gemcitabine-based chemotherapy, or fluoropyrimidine-based CRT are acceptable options.

For patients with positive margins or positive regional lymph nodes, options include fluoropyrimidine- or gemcitabine-based chemotherapy, fluoropyrimidine-based CRT, or a combined approach.

Intrahepatic cholangiocarcinoma:

For no residual local disease, options include observation or fluoropyrimidine- or gemcitabine-based chemotherapy alone.

For patients with positive margins or positive regional nodes, options include fluoropyrimidine- or gemcitabine-based chemotherapy, fluoropyrimidine-based CRT, or a combined approach.

Guidelines from the European Society of Medical Oncology (ESMO) for treatment of either intrahepatic or extrahepatic cholangiocarcinoma suggest that in the absence of level 1 data, the multidisciplinary team may offer adjuvant therapy (RT, CRT, or chemotherapy alone) to patients based on the best available evidence and only after a risk-benefit assessment [131].

NEOADJUVANT APPROACHES

Indications — Preoperative chemoradiotherapy (CRT) or chemotherapy is not a standard approach to treatment of cholangiocarcinoma. However, neoadjuvant therapy has been used in the following settings:

Sometimes, patients with large, locally advanced unresectable intrahepatic cholangiocarcinomas who are treated with initial CRT or chemotherapy (eg, gemcitabine/cisplatin) can be converted to potentially resectable disease; such patients may be evaluated for resection in this setting. (See "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma", section on 'Reassessment for resectability'.)

Orthotopic liver transplantation (OLT) is not a standard form of therapy for localized cholangiocarcinoma at present. However, in the context of a clinical trial, OLT is an option for highly selected patients with early-stage cholangiocarcinoma arising in the setting of primary sclerosing cholangitis (PSC) or those with small (<3 cm) but locally unresectable hilar cholangiocarcinomas who have successfully completed rigorous staging and neoadjuvant therapy. Such clinical protocols are accepted and reviewed by the United Network for Organ Sharing (UNOS), and are available at a growing number of transplant centers.

Benefit

Prior to resection — Neoadjuvant therapy is often not an option for patients with potentially resectable cholangiocarcinoma, the majority of whom are jaundiced and have a poor functional status at presentation. However, the potential benefit of this approach for selected patients with extrahepatic cholangiocarcinoma has been suggested by the following small reports:

In an early series of nine (out of a total of 91) patients with extrahepatic cholangiocarcinoma who underwent preoperative CRT prior to exploration, three had a pathologic complete response while the remainder showed different degrees of histologic response to treatment [132]. Margin-negative resections were possible in all nine patients as compared with only one-half of those who did not receive neoadjuvant therapy.

Benefit for neoadjuvant CRT was also suggested in a report of 45 patients undergoing concurrent CRT in resected extrahepatic cholangiocarcinoma, of whom 12 were treated neoadjuvantly [107]. Three had a complete pathologic response, and 11 were able to undergo a complete (R0) resection. Despite having more advanced disease at presentation, patients who received neoadjuvant CRT had longer five-year survival (53 versus 23 percent), and rates of grade 2 to 3 surgical morbidity were no higher (16 versus 33 percent) compared with those treated in the postoperative setting.

These promising early results support the need for randomized trials testing this strategy [133].

Prior to orthotopic liver transplantation — Some centers offer OLT for highly selected patients with early-stage cholangiocarcinoma arising in the setting of PSC or for those with early stage, small, but unresectable perihilar cholangiocarcinomas who have successfully completed rigorous staging and neoadjuvant therapy. However, in our view, given the highly selected nature of these patients, the poor sensitivity of noninvasive staging for cholangiocarcinoma, and issues with donor allocation, OLT remains a controversial treatment for cholangiocarcinoma that should only be carried out after careful evaluation at experienced centers in the context of a UNOS-approved protocol.

Available data — OLT has been evaluated as a treatment for intrahepatic and central cholangiocarcinomas in retrospective series with mixed results [134-150]. A significant limitation of the data is that up to 15 percent of patients might not have had malignancy; in many cases the patients were transplanted for PSC without a known diagnosis of cancer, and they were found to have incidental cholangiocarcinomas in their native liver, or they did not have disease confirmed prior to neoadjuvant therapy by either cytology, fluorescence in situ hybridization (FISH), or subsequent disease relapse [151].

A 2011 systematic review of 14 published reports (totaling 605 transplanted patients) on the safety and efficacy of liver transplantation for cholangiocarcinoma came to the following conclusions [152]:

The overall pooled one-, three-, and five-year survival rates were 73, 42, and 39 percent, respectively. Outcomes were more favorable among patients who had received neoadjuvant therapy prior to transplantation (pooled one-, three-, and five-year survival 83, 57, and 65 percent, respectively).

The overall pooled incidence of complications was 62 percent (95% CI 44-78 percent), and it was higher in those undergoing transplantation followed by extended bile duct resection (78 percent, 95% CI 55-94 percent).

The authors concluded that well-designed, prospective randomized controlled studies were needed to confirm the place of transplantation in cholangiocarcinoma.

The following sections will review the available data in two distinct populations, individuals with initially unresectable tumors and those with potentially resectable tumors.

Initially unresectable disease — Interest in OLT as a treatment for initially unresectable cholangiocarcinoma was revived by the published experience of the Mayo Clinic, which reported a five-year survival rate of 82 percent in a series of patients with initially unresectable cholangiocarcinoma arising in the setting of PSC who were treated with preoperative CRT followed by exploratory laparotomy to exclude metastatic disease before transplantation [135]. Of concern, however, 7 of the 16 explants that contained no viable tumor after CRT did not have a pretreatment cytologic diagnosis, raising questions as to incorrect diagnosis in these patients. Furthermore, these results do not reflect an "intention to treat" analysis. A more recent report of the Mayo experience using an intent to treat analysis (of all patients who were enrolled in the protocol regardless of whether they were transplanted or not) revealed one-, three-, and five-year survival rates of 82, 63, and 55 percent, respectively [144].

The impact of neoadjuvant therapy was addressed in a year 2021 meta-analysis of survival after OLT for unresectable perihilar cholangiocarcinoma (20 studies, 428 transplanted patients), which came to the following conclusions [153]:

The pooled one-, three-, and five-year overall survival rates following OLT without neoadjuvant therapy were 71, 48, and 32 percent, respectively; the corresponding rates with neoadjuvant CRT were 83, 65, and 65 percent, respectively.

The pooled three-year recurrence rate was 24 percent with neoadjuvant CRT, and 57 percent without it.

Insufficient studies were available to assess whether the proportion of patients transplanted with PSC affected outcomes.

An important limitation is that patient selection criteria differed among the 20 studies included in the analysis.

Initially resectable disease — More recently, experience has accrued with OLT in patients with potentially resectable cholangiocarcinoma; in almost all of these cases, patients have been initially treated with neoadjuvant therapy [150,154,155]:

A retrospective review of the experience with neoadjuvant CRT followed by OLT for localized cholangiocarcinoma at 12 United States centers (with 193 of the 287 patients coming from the Mayo Clinic) demonstrated two- and five-year survival rates of 68 and 53 percent, respectively, in an intent to treat analysis [154].

A multi-institutional retrospective series included 304 patients with suspected hilar cholangiocarcinoma who were treated over a 15-year period at 10 institutions; 234 had resection, and 70 were enrolled in a transplant protocol [150]. Excluding macroscopically incomplete (R2) resections, those who never underwent the transplant, and those who had OLT without a confirmed diagnosis of cholangiocarcinoma left 191 patients undergoing curative-intent resection and 41 undergoing curative-intent transplant. Transplanted patients more often had PSC (61 versus 2 percent) and more often received chemotherapy and/or radiotherapy (98 versus 57 percent). Transplanted patients had improved survival over resection alone at both three (72 versus 33 percent) and five years (64 versus 18 percent). Even among patients who underwent resection for tumors <3 cm with lymph node-negative disease and excluding PSC patients, transplant was still associated with better overall survival (at five years, 54 versus 29 percent).

There are no randomized trials investigating the role of OLT as compared with resection in these patients. While the retrospective data seem promising, the better results with transplantation might simply reflect patients with a better performance status or more favorable tumor biopsy being offered OLT. Prospective randomized trials are needed, and such a trial, the French TRANSPHIL study (NCT02232932), has completed accrual and is awaiting maturation of the data.

Whether outcomes from OLT are better in patients with underlying PSC is unclear. Outcomes in patients with cholangiocarcinoma in the setting of PSC were described in 13 reports with a total of 91 patients. When combining results of the largest four studies, 53 percent recurred. A study of patients with an incidental cholangiocarcinoma found in the setting of PSC (published after the systematic review) found one-, three- and five-year survival rates of 65, 35, and 35 percent, respectively [137].

Issues related to organ allocation — The allocation of organs for patients with cholangiocarcinoma is based on the Model for End-Stage Liver Disease (MELD) score, and no priority or exception is given unless a center submits a written protocol detailing its selection criteria, administration of neoadjuvant therapy before transplantation, and operative staging to exclude patients outside of transplant criteria to the Organ Procurement and Transplantation Network (OPTN)/UNOS Liver and Intestinal Organ Transplantation Committee [156]. UNOS has established criteria for MELD exception for liver transplantation candidates with early unresectable hilar cholangiocarcinoma who complete an approved protocol that includes neoadjuvant therapy, with strict inclusion and exclusion criteria (policy 3.6.4.5.2 Liver Candidates with Cholangiocarcinoma) [156]. The MELD exception score was set to 22, equal to the standard assigned score for hepatocellular carcinoma, with eligibility for an increased score every three months if the criteria are still met. There is no accurate information on how many centers in the United States are actively transplanting these patients, what type of neoadjuvant therapy is being used, and outcomes.

Patient selection — There is no consensus as to the optimal criteria for patient selection for this approach. Criteria for neoadjuvant therapy and liver transplantation from the Mayo Clinic include the following [148]:

Diagnosis of cholangiocarcinoma (transcatheter biopsy or brush cytology; CA 19-9 >100 mg/mL and/or a mass on cross-sectional imaging with a malignant-appearing stricture on cholangiography; biliary ploidy by fluorescence in situ hybridization [FISH] with a malignant-appearing stricture on cholangiography)

Unresectable tumor above the cystic duct (pancreatoduodenectomy for microscopic involvement of the common bile duct; or resectable cholangiocarcinoma arising in a patient with PSC)

Radial tumor diameter ≤3 cm

Absence of intra- and extrahepatic metastases

Candidate for liver transplantation

SUMMARY AND RECOMMENDATIONS

Surgical treatment and prognosis

Cholangiocarcinomas may arise from the epithelial cells of the intrahepatic or extrahepatic bile ducts. Surgery is a prerequisite for cure; however, only a minority of patients are candidates for resection. Furthermore, outcomes after resection are poor, particularly with node-positive disease. (See 'Overview of surgical treatment and prognosis' above.)

Preoperative imaging is used to diagnose and accurately stage cholangiocarcinomas; however, true resectability is ultimately determined at surgery, particularly with perihilar tumors. (See 'Preoperative assessment and criteria for resectability' above.)

Adjuvant therapy

Patients with resected cholangiocarcinoma should be encouraged to enroll in randomized trials testing various adjuvant therapy strategies.

Off-protocol, we suggest adjuvant therapy for all patients following resection of an intrahepatic or extrahepatic cholangiocarcinoma (Grade 2C).

-For individuals with resected extrahepatic cholangiocarcinoma who have microscopically positive resection margins or a microscopically complete (R0) resection with node-positive disease, and for patients with a margin-positive intrahepatic cholangiocarcinoma, we suggest postoperative adjuvant chemotherapy plus chemoradiotherapy (CRT) rather than chemotherapy alone (Grade 2C).

-For others, we suggest chemotherapy alone (Grade 2C). (See 'Rationale for adjuvant therapy' above.)

The choice of the specific regimen is empiric; there are no trials directly comparing gemcitabine-based with fluorouracil (FU)-based chemotherapy regimens, with or without concurrent CRT. Acceptable options for patients receiving CRT include the following (see 'Choice of regimen' above):

-Concurrent radiotherapy (RT) plus infusional FU (225 mg/m2 daily), followed by an additional four months capecitabine alone (1000 mg/m2 twice daily for 14 of every 21 days).

-Four cycles of capecitabine plus gemcitabine followed by concurrent RT plus oral capecitabine (1330 mg/m2 per day, divided into two daily doses) (table 6).

-Three weeks of gemcitabine alone followed by concurrent FU-based CRT and three additional months of gemcitabine monotherapy, as is used in the adjuvant setting for pancreatic cancer. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Gemcitabine-based approaches'.)

For patients not receiving CRT, we suggest six months of chemotherapy alone (Grade 2C). Options include (see 'Choice of regimen' above):

-Capecitabine alone (starting at a 1500 mg total dose twice daily on days 1 to 14 every 21 days)

-Single-agent gemcitabine (table 7)

-Leucovorin-modulated FU (table 8)

-S-1, where available.

Hepatic artery-based therapies, particularly radioembolization, appear promising for patients with locally advanced unresectable intrahepatic cholangiocarcinoma. However, there is insufficient evidence for any of these techniques after complete resection of an intrahepatic cholangiocarcinoma, except in the setting of a clinical trial. (See 'Hepatic artery-based therapies for intrahepatic cholangiocarcinoma' above.)

Neoadjuvant therapy

Preoperative (neoadjuvant) CRT is not a standard approach to treatment of cholangiocarcinoma. Rarely, patients with large, locally advanced unresectable cholangiocarcinomas who are treated with CRT are converted to potentially resectable disease; such patients may be evaluated for resection in this setting. (See 'Neoadjuvant approaches' above.)

Orthotopic liver transplantation (OLT) is an option for highly selected patients with early-stage cholangiocarcinoma arising in the setting of primary sclerosing cholangitis or for those with early stage, small, but unresectable hilar cholangiocarcinomas who have successfully completed rigorous staging and neoadjuvant therapy. In our view, OLT should only be carried out after careful evaluation at experienced centers, preferably within the context of a clinical trial. (See 'Prior to orthotopic liver transplantation' above.)

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Topic 2467 Version 67.0

References

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