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Systemic therapy for advanced unresectable and metastatic gallbladder cancer

Systemic therapy for advanced unresectable and metastatic gallbladder cancer
Authors:
Bhoomi Mehrotra, MD
Tanios Bekaii-Saab, MD
Section Editor:
Richard M Goldberg, MD
Deputy Editor:
Sonali M Shah, MD
Literature review current through: Apr 2025. | This topic last updated: Mar 18, 2025.

INTRODUCTION — 

Gallbladder cancer (GBC) is an uncommon malignancy with a poor prognosis. This is thought to be related to advanced stage at diagnosis, which is due both to the anatomic position of the gallbladder and to the vagueness and nonspecificity of symptoms. (See "Epidemiology, risk factors, clinical features, and diagnosis of gallbladder cancer", section on 'Clinical presentation'.)

Surgery is the only potentially curative treatment for patients with GBC. However, few patients are eligible for curative-intent surgery because of disease extent, such as local invasion into critical structures or distant metastases. (See "Adjuvant therapy for localized resected gallbladder cancer".)

Therefore, systemic therapy is used to treat most patients with advanced unresectable or metastatic GBC. The goals of treatment are palliative, including relief of cancer-related symptoms (such as pain, jaundice, and bowel obstruction) and prolongation of life.

This topic discusses systemic therapy for advanced unresectable and metastatic GBC. The clinical presentation and diagnosis of GBC and the management of advanced bile duct cancer (cholangiocarcinoma) are discussed separately.

●(See "Epidemiology, risk factors, clinical features, and diagnosis of gallbladder cancer".)

●(See "Treatment of locally advanced unresectable nonmetastatic cholangiocarcinoma".)

●(See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma".)

INTERVENTIONS FOR OBSTRUCTIVE JAUNDICE — 

For patients with advanced GBC and associated obstructive jaundice, endoscopic or percutaneous biliary stenting is generally preferred at most institutions if appropriate expertise is available, given that most patients have disseminated, incurable disease and limited survival. Such interventions for obstructive jaundice may improve total bilirubin levels, which in turn could allow patients to initiate appropriate systemic therapy with agents that require hepatic metabolism. (See 'Initial systemic therapy' below.)

Jaundice caused by biliary obstruction is the presenting feature in 30 to 60 percent of patients with GBC; the usual cause is direct infiltration of the common hepatic duct by tumor [1]. Preoperative jaundice is a relative contraindication to radical resection as the majority of patients presenting with jaundice will have disseminated disease. However, consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest that neoadjuvant chemotherapy could be "considered" in this situation [2]. (See "Surgical management of gallbladder cancer", section on 'Unresectable disease'.)

Although biliary or intestinal bypass can successfully palliate obstructive jaundice [3], stenting via a percutaneous or endoscopic approach is generally preferred given the limited survival in patients with advanced disease (generally less than six months). Drainage of as little as 30 percent of the liver parenchyma (as can be accomplished with unilateral drainage of one lobe of the liver) may be sufficient to adequately palliate jaundice and relieve pruritus.

Most stents are placed endoscopically. Although endoscopic methods appear to be better than percutaneous drainage in patients with lower bile duct obstruction caused by pancreatic and periampullary cancers, success rates may be lower and complication rates (particularly cholangitis) higher with the endoscopic approach in patients with more proximal (including hilar) obstruction. (See "Endoscopic stenting for malignant biliary obstruction".)

Percutaneous and endoscopic approaches to biliary drainage were directly compared in a trial in which 54 consecutive patients with GBC and Bismuth type II or III biliary obstruction (figure 1) who were not suitable for resection were randomly assigned to percutaneous transhepatic biliary drainage or endoscopic stenting [4]. Successful drainage was more often achieved with percutaneous drainage (89 versus 41 percent), while early cholangitis was a more common complication of endoscopic stenting (48 versus 11 percent). Rates of stent occlusion (32 versus 39 percent) and median survival (60 days in both groups) were not significantly different.

However, the success rate with endoscopic drainage in this study (41 percent) was much lower than that usually seen in clinical practice, and it is not surprising that this group had a higher complication rate due to the high rate of unsuccessful instrumentation of an obstructed biliary system. Other complications may be more frequent with the percutaneous approach (eg, bile leaks and bleeding), potentially increasing morbidity and mortality [5,6]. Furthermore, percutaneous stents often cannot be internalized and require attachment of an inconvenient external collection reservoir. As a result, in most institutions, an initial endoscopic attempt at drainage is usually preferred, as long as local endoscopic expertise is available. (See "Endoscopic stenting for malignant biliary obstruction".)

INITIAL SYSTEMIC THERAPY — 

Patients with previously untreated advanced unresectable or metastatic GBC may be offered systemic therapy.

The approach to initial systemic therapy in advanced and metastatic GBC is evolving. Given the rarity of this disease, high-quality studies on initial management are limited. Most studies consist of a heterogeneous population of patients with GBC, cholangiocarcinoma, and occasionally some pancreatic and hepatic cancers [7-10]. Therefore, we encourage enrollment in clinical trials, where available.

Our approach to initial therapy is based on patient performance status and bilirubin levels. Of note, most studies are conducted in patients with adenocarcinoma, which is the most common histology of GBC. Patients with advanced adenosquamous or squamous cell GBCs are managed similarly to those with adenocarcinoma since there are limited data for the treatment of these rare histologies. The treatment of patients with advanced small cell carcinoma of the gallbladder is discussed separately. (See "Extrapulmonary small cell cancer", section on 'Gallbladder ESCC'.)

Good performance status and no hyperbilirubinemia — For patients with advanced unresectable or metastatic GBC with good Eastern Cooperative Oncology Group performance status (less than 2 (table 1)) and no hyperbilirubinemia, we suggest initial therapy with the addition of immunotherapy (either durvalumab or pembrolizumab) to gemcitabine plus cisplatin. Although either chemoimmunotherapy regimen is appropriate, gemcitabine plus cisplatin and durvalumab has the advantage of a simpler maintenance regimen with single-agent durvalumab every four weeks, which may be preferred by some patients and providers. (See 'Gemcitabine plus cisplatin and durvalumab' below and 'Gemcitabine plus cisplatin and pembrolizumab' below.)

Gemcitabine plus cisplatin and durvalumab — The addition of durvalumab to gemcitabine plus cisplatin is an option for initial therapy in patients with treatment-naive advanced or metastatic GBC and no hyperbilirubinemia. In a phase III trial, this combination improved overall survival (OS) with durable responses and was well-tolerated [11,12]. After completion of induction chemoimmunotherapy, maintenance therapy consists of single-agent durvalumab every four weeks until disease progression or unacceptable toxicity.

Gemcitabine plus cisplatin and durvalumab was investigated in a double-blind, placebo-controlled phase III trial (TOPAZ-1) of 685 patients with previously untreated, unresectable locally advanced or metastatic biliary tract cancer. Patients had either intrahepatic cholangiocarcinoma (56 percent), extrahepatic cholangiocarcinoma (19 percent), or GBC (25 percent) [11,12]. For all patients, total bilirubin was less than 2.5 times the upper limit of normal (ULN). Patients were randomly assigned to receive either durvalumab (1500 mg every three weeks) or placebo in combination with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8 every three weeks for up to eight cycles. Patients subsequently received maintenance therapy with either durvalumab (1500 mg every four weeks) or placebo until disease progression or unacceptable toxicity.

At a median follow-up of 23 months, relative to placebo plus chemotherapy, durvalumab plus gemcitabine and cisplatin improved OS in the entire study population (median 12.9 versus 11.3 months, hazard ratio [HR] 0.76, 95% CI 0.64-0.91) [12]. This OS benefit was generally seen across clinically relevant subgroups, including those with GBC (HR 0.90). Treatment with chemoimmunotherapy was also well tolerated. Full results of this trial for the entire study population are discussed separately. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Gemcitabine plus cisplatin and durvalumab'.)

Based on these data, the US Food and Drug Administration (FDA) approved durvalumab, in combination with gemcitabine and cisplatin, for adult patients with locally advanced or metastatic biliary tract cancers [13].

Gemcitabine plus cisplatin and pembrolizumab — The addition of pembrolizumab to gemcitabine plus cisplatin is an option for initial therapy in patients with advanced or metastatic GBC. In a phase III trial, this combination improved OS with durable responses and was well-tolerated [14]. After completion of induction chemoimmunotherapy, maintenance therapy for most patients consisted of both gemcitabine and pembrolizumab for up to 35 cycles (two years), including induction cycles, followed by gemcitabine monotherapy until disease progression or unacceptable toxicity.

Gemcitabine plus cisplatin and pembrolizumab was evaluated in a double-blind, placebo-controlled phase III trial (KEYNOTE-966) of 1069 patients with previously untreated locally advanced or metastatic biliary tract cancer, including intrahepatic (59 percent) or extrahepatic cholangiocarcinoma (19 percent) and GBC (25 percent) [14]. In this study, patients were randomly assigned to either pembrolizumab (200 mg every three weeks) or placebo, in combination with gemcitabine (1000 mg/m2 on days 1 and 8 every three weeks) plus cisplatin (25 mg/m2 on days 1 and 8 every three weeks) for up to eight cycles. For maintenance therapy, gemcitabine could be continued with no maximum duration, and pembrolizumab or placebo was continued for up to 35 cumulative cycles (two years), or until disease progression or unacceptable toxicity. Patients who discontinued gemcitabine, cisplatin, or both due to toxicity could continue pembrolizumab or placebo, and vice-versa.

At a median follow-up of 26 months, compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved OS in the entire study population (median OS 12.7 versus 10.9 months, two-year OS 25 versus 18 percent, HR 0.83, 95% CI 0.72-0.95) [14]. This OS benefit was generally seen across all clinically relevant subgroups, including those with GBC (HR 0.96). Treatment with chemoimmunotherapy was also well tolerated. Full results of this trial for the entire study population and other subgroups are discussed separately. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Gemcitabine plus cisplatin and pembrolizumab'.)

Gemcitabine plus cisplatin and pembrolizumab is approved by the FDA for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer [13].

Gemcitabine plus cisplatin — Gemcitabine plus cisplatin (table 2) is an appropriate alternative for patients with treatment-naïve advanced GBC, good performance status, and no hyperbilirubinemia (ie, total bilirubin less than 2.5 times the ULN) who decline chemoimmunotherapy or are anticipated to not tolerate its toxicities. Gemcitabine plus cisplatin improved OS over single-agent gemcitabine in a randomized trial [15] and is a well-tolerated regimen [16]. However, few studies have directly compared it with other gemcitabine-based combinations.

Initial studies suggested clinical efficacy for the use of gemcitabine plus cisplatin in patients with advanced or metastatic GBC [17-19]. Gemcitabine plus cisplatin was subsequently evaluated in an open-label phase III trial (ABC-02) of 410 patients with locally advanced or metastatic bile duct (59 percent), gallbladder (36 percent), or ampullary (5 percent) cancer [15]. In this study, patients were randomly assigned to 24 weeks of either gemcitabine (1000 mg/m2) plus cisplatin (25 mg/m2) on days 1 and 8 every 21 days, or gemcitabine alone (1000 mg/m2 on days 1, 8, and 15 every 28 days).

At a median follow-up of approximately eight months, compared with gemcitabine alone, the combination improved OS (median 11.7 versus 8.1 months, HR 0.64, 95% CI 0.52-0.80) in the entire study population [15]. This OS benefit was seen in all relevant subgroups including those with GBC (HR 0.61, 95% CI 0.42-0.89). Toxicity was similar in both treatment arms, except for higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin. Further results of this trial for the entire study population and other subgroups are discussed separately. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Gemcitabine plus cisplatin'.)

Few randomized trials have directly compared gemcitabine plus cisplatin with other gemcitabine-based combinations. These results are discussed separately. (See 'Gemcitabine plus S-1' below and 'Gemcitabine plus oxaliplatin' below.)

Other regimens — Other options for initial therapy include gemcitabine plus oxaliplatin, gemcitabine plus capecitabine, gemcitabine plus carboplatin, gemcitabine plus fluorouracil (FU), and gemcitabine plus S-1 (where available).

Gemcitabine plus oxaliplatin — GEMOX (table 3) is an alternative to gemcitabine plus cisplatin and gemcitabine plus capecitabine or S-1 for treatment of advanced, unresectable GBC. Antitumor efficacy and good tolerability for GEMOX have been reported in several (but not all [20]) studies [21-24]. Most utilized gemcitabine 1000 mg/m2 on days 1, 8, and 15 plus oxaliplatin 100 mg/m2 on days 1 and 15 of every 28-day cycle, or gemcitabine 1000 mg/m2 on day 1 plus oxaliplatin 100 mg/m2 on day 1 or 2 of every 21-day cycle. The following data are available:

●A representative phase II study reported on 31 previously untreated patients with advanced biliary cancer (19 with GBC) who had a good performance status and a serum bilirubin level <2.5 times the ULN. The response rate was 36 percent, and median OS duration was 14.3 months using every-other-week gemcitabine (1000 mg/m2 on day 1) and oxaliplatin (100 mg/m2 on day 2) [21]. Results were less favorable in 25 other patients treated on the same protocol who had a poorer performance status, who were receiving second- or third-line therapy, or who had a higher bilirubin level (response rate 22 percent, median survival 7.6 months).

●In a randomized phase III noninferiority trial directly comparing GEMOX versus CAPOX in 222 patients receiving first-line chemotherapy for advanced biliary tract cancer (27 percent GBC), there were two complete and 26 partial responses with GEMOX (objective response rate 25 percent), and no complete and 17 partial responses with CAPOX (objective response rate 16 percent). Despite this difference, median OS was similar in both groups (10.4 versus 10.6 months), as was the six-month progression-free survival rate (45 versus 47 percent) [24]. The authors concluded that CAPOX was noninferior to first-line GEMOX.

●A modified version of GEMOX (oxaliplatin 80 mg/m2 plus gemcitabine 900 mg/m2, both on days 1 and 8 of every 21 days (table 4)) was directly compared with gem/cis in a single-center phase III trial of 260 patients with chemotherapy-naive unresectable or metastatic GBC conducted in India [25]. At a median follow-up of 10.5 months, the objective response rates were no different (23 versus 24 percent), and median OS was also similar (eight versus nine months). Toxicity was comparable, with the exception of more grade 3 or 4 diarrhea and thrombocytopenia and more grade 1 or 2 peripheral neuropathy with modified GEMOX.

Gemcitabine plus capecitabine — Gemcitabine plus capecitabine (table 5) is an active, well-tolerated regimen in advanced biliary tumors, including GBC. Based on data from phase II trials that included advanced GBC, gemcitabine plus capecitabine demonstrated objective response rates of approximately 25 to 30 percent and median OS between 13 and 16 months [26-30]. Although gemcitabine plus capecitabine is a reasonable alternative for initial therapy, it has not been directly compared with gemcitabine plus cisplatin in randomized trials.

Gemcitabine plus carboplatin — The substitution of carboplatin for cisplatin reduces the severity of nonhematologic toxicity, but myelosuppression is sometimes worse. In a trial involving 20 patients with advanced GBC, the response rate with 21-day cycles of gemcitabine (1000 mg/m2 on days 1 and 8) plus carboplatin (administered at an area under the curve of concentration x time [AUC] of 5 on day 1 according to the Calvert formula [carboplatin dose (mg) = target AUC X (estimated creatinine clearance + 25)]) was 37 percent, and there were four complete responders [31]. Median OS was approximately 11 months. Treatment was well tolerated, with grade 3 or 4 neutropenia in only 20 percent, vomiting or diarrhea in 12 and 9 percent, respectively, stomatitis in 5 percent, and thrombocytopenia in 5 percent.

However, there is marked interindividual variability in the hematologic tolerance of this combination. A pharmacokinetic analysis suggested that in combination with gemcitabine, dosing of carboplatin at an AUC of 5 was associated with grade 3 or 4 thrombocytopenia rates of 38 and 31 percent for pretreated and non-pretreated patients, respectively [32].

Dosing of carboplatin is discussed in detail separately. (See "Dosing of anticancer agents in adults", section on 'Carboplatin'.)

Gemcitabine plus fluorouracil and leucovorin — Whether adding treatment with FU and leucovorin (LV) to gemcitabine augments benefit over gemcitabine alone remains an open question. In a multicenter phase II trial involving 40 patients with biliary cancers (22 with GBC), gemcitabine (1000 mg/m2 weekly for three of every five weeks) was given alone (n = 18), or gemcitabine (1000 mg/m2 on days 1 and 8 every 21 days) was given with FU (400 mg/m2 bolus followed by 22-hour infusion of 600 mg/m2 every 21 days) and LV (100 mg/m2 over two hours on day 1 every 21 days; n = 22) [33]. Partial responses were noted in 22 and 36 percent of patients receiving gemcitabine alone or with FU and LV, respectively, and the median times to progression were 3.4 and 4.1 months, respectively. Toxicity was mild and manageable, particularly with gemcitabine alone.

A second multicenter phase II trial of gemcitabine plus FU and LV reported three partial responses among 14 cases of GBC (objective response rate 21 percent), and the median time to progression and OS were 5.2 and 7.2 months, respectively [34].

Gemcitabine plus S-1 — Gemcitabine plus S-1 is an option for initial treatment of advanced unresectable or metastatic GBC that was noninferior to gemcitabine plus cisplatin in a randomized trial [35]. S-1, which is available in some countries outside the United States, is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of the FU-metabolizing enzyme dihydropyridine dehydrogenase [DPD]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea).

In a phase III noninferiority trial (FUGA-BT) conducted in Japan, 354 patients with chemotherapy-naïve recurrent or unresectable adenocarcinoma of the gallbladder, biliary tract, or ampulla of Vater were randomly assigned to either gemcitabine (1000 mg/m2 on days 1 and 8) plus S-1 (60, 80, or 100 mg daily based upon body surface area and administered from days 1 to 14 of a 21-day cycle) or gemcitabine plus cisplatin [35]. For the entire study population, relative to gemcitabine plus cisplatin, gemcitabine plus S-1 was noninferior for OS. In a subgroup analysis of the 137 patients with GBC, gemcitabine plus S-1 was also noninferior for OS relative to gemcitabine plus cisplatin (HR 0.97, 95% CI 0.64-1.40). Both agents were similarly well-tolerated. Further details of this trial for the entire study population and other patient subgroups are discussed separately. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Gemcitabine plus S-1'.)

Non-gemcitabine-based regimens — Several older small randomized trials have directly compared a gemcitabine-containing with a non-gemcitabine-containing chemotherapy regimen (typically fluoropyrimidine monotherapy) or chemoradiation (CRT) for first-line therapy of advanced biliary tract cancer [36-41]. A year 2018 Cochrane analysis concluded that the evidence obtained from these low-quality trials was insufficient to prove whether or not gemcitabine-containing combinations are better than non-gemcitabine-containing combinations [42]. Additional randomized trials are needed with gem/cis as the control arm.

Some data suggest potential benefit from more aggressive combination chemotherapy regimens such as oxaliplatin, irinotecan, LV plus short-term infusional FU (FOLFIRINOX), but the higher than expected response rates have also been accompanied by significant toxicity, especially involving the gastrointestinal tract [43]. The absence of a control group receiving a gemcitabine-containing combination regimen makes it difficult to ascertain whether the benefits of more aggressive combination therapy outweigh the risks. Randomized trials are needed.

Good performance status and persistent biliary obstruction — For patients with good performance status and persistent hyperbilirubinemia despite stenting, we prefer a non-gemcitabine-based regimen, such as LV-modulated FU (table 6) or a fluoropyrimidine plus oxaliplatin combination.

In prior studies, objective response rates for FU alone or FU-based combination therapies ranged from 0 to 34 percent, and median survival was typically less than six months [44-46]. Many, but not all, more contemporary observational series using either infusional FU in combination regimens or LV-modulated FU report higher response rates and marginally longer survival (but still less than one year) [47-51].

Fluoropyrimidine plus oxaliplatin — One active non-gemcitabine-containing regimen is CAPOX (table 7):

●In one trial, CAPOX was administered to 65 evaluable patients with biliary tract tumors, 27 with GBC, and the remainder with cholangiocarcinoma [52]. Of the 27 patients with GBC, there was one complete and seven partial responses; an additional nine had stable disease (total disease control rate 63 percent). Median survival was 11.3 months. Treatment was well tolerated, with only mild hematologic toxicity, grade 3 or 4 peripheral neuropathy in 11 patients in the entire cohort, and two hypersensitivity reactions to oxaliplatin.

●In a randomized phase III noninferiority trial directly comparing GEMOX versus CAPOX in 222 patients receiving first-line chemotherapy for advanced biliary tract cancer, there were two complete and 26 partial responses with GEMOX (objective response rate 25 percent), and no complete and 17 partial responses with CAPOX (objective response rate 16 percent). Despite this difference, median OS was similar in both groups (10.4 versus 10.6 months), as was the six-month progression-free survival rate (45 versus 47 percent) [24]. The authors concluded that CAPOX was noninferior to first-line GEMOX.

Another active regimen, which has been mainly studied for second-line therapy after failure of gemcitabine plus a platinum agent, is oxaliplatin plus LV and short term-infusional FU (FOLFOX) (table 8) [53,54]. (See 'Second-line therapy' below.)

Infusional fluorouracil plus cisplatin — Infusional FU has been combined with cisplatin in at least two trials. In one, FU (1000 mg/m2 by continuous infusion daily for five days) plus cisplatin (100 mg/m2 on day 2) resulted in partial remission in six patients (24 percent); one was a long-term survivor after receiving additional local therapy [47]. Median survival for patients with GBC was 11.5 months.

In the second report, FU (200 mg/m2 per day by continuous intravenous infusion throughout the treatment) was given with epirubicin (50 mg/m2) plus cisplatin (60 mg/m2 on day 1) with cycles repeated every 21 days (the ECF regimen) [51]. The objective response rate was 40 percent, and the median duration of response was 10 months. A somewhat lower response rate was noted in a subsequent phase III trial that showed similar therapeutic efficacy for ECF as compared with FU plus LV and etoposide (objective response rate 19 versus 15 percent, median OS 9 versus 12 months, respectively) [55]. ECF was associated with significantly less acute toxicity.

Borderline performance status — For patients with a borderline performance status or extensive comorbidities, we suggest gemcitabine monotherapy (table 9). Other alternatives are capecitabine monotherapy, FU plus LV (table 6), or biweekly cisplatin plus gemcitabine. Supportive care alone is also an appropriate alternative.

Reported clinical benefit rates (partial response plus stable disease) with single-agent gemcitabine (1000 to 1200 mg/m2 weekly for three of every four weeks) are in the range of 15 to 60 percent, although objective response rates are as low as 7 percent [9,56-58]. In most studies, median survival is 11 months or less.

Capecitabine, an orally active fluoropyrimidine derivative, appears to be an active agent for GBC as a single agent. In a report of 63 patients with hepatobiliary malignancies, which included eight patients with GBC, capecitabine (2000 mg/m2 daily for 14 of every 21 days) produced an objective response in four (50 percent) of the patients with GBC, two of which were complete [8]. By contrast, there were no responses among those with cholangiocarcinoma.

Other options include biweekly gemcitabine plus cisplatin, which is associated with a more favorable toxicity profile than standard gemcitabine plus cisplatin [59], or FU plus LV (table 6) [49,50]. (See 'Gemcitabine plus cisplatin' above.)

SECOND-LINE THERAPY — 

There are few prospective trials comparing specific treatment regimens in the second-line setting for advanced biliary tract cancer, and the selection of second-line therapy as well as the optimal regimens are not established. We generally choose a second line regimen that does not overlap with the agents used as part of initial therapy. Clinical trial enrollment is encouraged, where available.

Selecting candidates for second-line therapy — The optimal selection of candidates for second-line chemotherapy is not established [60]. Studies suggest that patients who have a good performance status (0 or 1 (table 1)), had disease control with first-line systemic therapy, have a relatively low cancer antigen 19-9 (CA 19-9) level, and possibly had previous surgery on their primary tumor have the longest survival with second-line chemotherapy [61,62], but it is not clear whether these characteristics predict responsiveness to systemic therapy or more favorable biologic behavior.

No actionable molecular alterations

FOLFOX — In the absence of a specific actionable molecular alteration, for most patients with metastatic GBC who progress on initial therapy that contains gemcitabine plus cisplatin and retain a good performance status, we suggest FOLFOX rather than other systemic regimens.

In an open-label phase III trial (ABC-06), 162 patients with advanced biliary tract cancer who progressed after gemcitabine plus cisplatin were randomly assigned to FOLFOX (table 8) plus active symptom control or active symptom control alone. The study included 117 patients with cholangiocarcinoma, 34 patients with GBC, and 11 patients with ampullary cancer [54]. At a median follow-up of 22 months, the addition of FOLFOX to active symptom control improved overall survival (OS; median 6.2 versus 5.3 months, hazard ratio [HR] 0.69, 95% CI 0.50-0.97). The grade ≥3 toxicity rate for FOLFOX was 69 percent, including neutropenia (12 percent), fatigue or lethargy (11 percent), and infection (10 percent).

Other regimens — Other chemotherapy regimens with defined activity in the second-line setting include gemcitabine plus capecitabine, if a non-gemcitabine-based regimen was used initially (table 5); a fluoropyrimidine alone, irinotecan alone [63,64], or CAPOX (table 7).

Regimens not used

●Liposomal irinotecan plus fluorouracil and leucovorin – We do not offer liposomal irinotecan in combination with fluorouracil (FU) and leucovorin (LV) in patients with metastatic GBC who progress on initial gemcitabine-based therapy. Initial data from a phase II trial (NIFTY-2) in a population of patients from South Korea with metastatic biliary tract cancer suggested clinical efficacy for this regimen [65]. However, in a separate randomized phase II trial (AIO NILIRICC) in patients from Western Europe with advanced cholangiocarcinoma and GBC, the addition of liposomal irinotecan to FU and LV failed to improve OS and worsened toxicity [66].

Actionable molecular alterations — Patients with metastatic GBC should be tested for mismatch repair deficiency (dMMR)/microsatellite instability (MSI), high tumor mutational burden (TMB-H), and other actionable molecular alterations. Those who progress on initial systemic therapy and have an actionable molecular alteration may be candidates for second- and later-line treatment with immunotherapy or molecularly targeted therapy.

Next-generation sequencing — All patients should undergo somatic (tumoral) genomic testing to determine eligibility for molecularly targeted therapy if they would be considered candidates for such therapy. ASCO has issued a provisional clinical opinion that supports somatic genomic testing in metastatic or advanced cancer when there are genomic biomarker-linked therapies approved by regulatory agencies for their cancer [67]. Given the tissue-agnostic approvals for any advanced cancer with a high tumor mutational burden or DNA mismatch repair deficiency (checkpoint inhibitor immunotherapy), or neurotrophic tyrosine receptor kinase (NTRK) fusions (TRK inhibitors), this provides a rationale for testing for all solid tumors, if the individual would be a candidate for these treatments. Testing should also be considered to determine candidacy for targeted therapies approved for other diseases in patients without an approved genomic biomarker-linked therapy; however, off-label/off-study use of such therapies is not recommended when a clinical trial is available, or without evidence of meaningful efficacy in clinical trials.

Several ongoing trials (eg, the NCI [National Cancer Institute] MATCH [Molecular Analysis for Therapy Choice] and the ASCO TAPUR [Targeted Agent and Profiling Utilization Registry] trials) are using next-generation sequencing of multiple genes (gene panel tests) to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or are regulatory approved either for the specific tumor of interest or other tumors. Such testing can be performed using next-generation sequencing. These tests can be used on formalin-fixed, paraffin-embedded (FFPE) tissue regardless of the primary organ from which the tumor arose. Where tumor genomic testing is not available, circulating tumor DNA (ctDNA) may be used [67]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management'.)

Targeted agents — Biliary tract carcinomas, including GBCs, have multiple molecular alterations, many of which are potential targets for available specific inhibitors. Promising targets for biliary tract cancers include fusions in the fibroblast growth factor receptor 2 (FGFR2) gene, alterations in the human epidermal growth factor 2 (HER2) gene, fusions in the neurotrophic tyrosine receptor kinase (NTRK) gene, dMMR/high levels of tumor mutational burden (TMB), and mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2. Notably, alterations in FGFR and IDH1 are more likely in intrahepatic cholangiocarcinoma than in GBC, while HER2 overexpression may be found more commonly with GBC than with cholangiocarcinoma.

The approach to second- and later-line therapy for advanced biliary tract cancers (including GBC) with specific targetable mutations is the same as those with advanced cholangiocarcinoma that harbor those mutations. Further details are presented separately. Specific information on immunotherapy for advanced GBC is presented below. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Molecularly targeted therapy'.)

Immunotherapy — Immune checkpoint inhibitors are an option for second- and later-line therapy in select patients with metastatic GBC and actionable molecular alterations that indicate responsiveness to these agents. (See "Principles of cancer immunotherapy".)

Biomarker-selected patients

●dMMR/MSI-H – The frequency of dMMR or MSI-H is approximately 5 percent for GBC [68], and approximately 4 percent of biliary tract cancers have high levels of TMB, with frequency being highest for GBC [69]. Diagnostic testing for dMMR/MSI-H is discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Diagnostic testing for dMMR/MSI-H'.)

Most patients with dMMR/MSI-H advanced GBC will be exposed to immunotherapy as part of earlier lines of therapy. For those that have been treated with all available therapies and have not received prior immunotherapy, either pembrolizumab [70] or dostarlimab are appropriate options. Further details are discussed separately. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Biomarker-selected patients' and "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Primary site-independent approaches'.)

●Tumor mutational burden – Biliary tract cancers are generally characterized by low TMB, with only 3 to 4 percent of cases having high levels of TMB (which has been defined variably) [71-74]. Diagnostic testing for TMB is discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Diagnostic testing for TMB'.)

Pembrolizumab is an option for patients with advanced TMB-H (≥10 mutations/Mb) gallbladder who have been treated with all available therapies and have not previously received immunotherapy. However, there are limited data in TMB-H advanced biliary tract tumors, including GBC [75,76]. Further details are discussed separately. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Biomarker-selected patients' and "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Pembrolizumab'.)

Biomarker-unselected patients — For patients with treatment-refractory metastatic GBC who do not have dMMR/MSI-H or high-levels of TMB, have been treated with all available standard therapies, and did not previously receive immunotherapy, options include either nivolumab plus ipilimumab or single-agent nivolumab due to the durable responses seen with these agents.

●Nivolumab plus ipilimumab – In an open-label phase II trial, 39 patients with biliary tract cancer (13 with GBC) were treated with nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) every three weeks for four doses followed by nivolumab (3 mg/kg) every two weeks [77]. Patients were unselected for biomarker expression, and 33 had previously received one or more lines of systemic therapy for advanced disease. In the subgroup of 13 patients with GBC, there were four objective responses (31 percent), with all responding patients treated in the second-line setting. All responders had proficient mismatch repair tumors. Duration of response ranged from 3 to 23 months or longer. Among the 39 patients with biliary tract cancer, the grade ≥3 toxicity rate was 15 percent. Similar results were seen in another phase II trial of 19 patients with pretreated advanced GBC treated with nivolumab (240 mg intravenous [IV] every two weeks) plus ipilimumab (1 mg/kg IV every six weeks), with an objective response rate of 16 percent and median duration of response of 15 months [78].

●Nivolumab – In a phase II trial of 54 patients with treatment-refractory metastatic biliary cancer, at a median follow-up of 12 months, nivolumab demonstrated an objective response rate of 22 percent (10 of 46 evaluable patients); all responses were in mismatch repair-proficient tumors [79]. The median duration of response was not reached. Median progression-free survival and OS were 4 and 14 months, respectively.

Angiogenesis inhibitors — Until more information becomes available, the use of angiogenesis inhibitors in patients with an advanced biliary tract malignancy, including GBC, should be considered experimental and should be limited to the context of a clinical trial.

Vascular endothelial growth factor (VEGF) is overexpressed in biliary tract cancers, including GBC, and has been proposed as a therapeutic target [80]. The efficacy of bevacizumab, a monoclonal antibody targeting VEGF, in combination with a variety of other drugs has been promising in uncontrolled studies in metastatic biliary tract cancer [81-84], but the contribution of bevacizumab to antitumor efficacy remains uncertain due to the lack of controlled trials.

The benefit of other treatments targeting angiogenesis (ie, regorafenib, ramucirumab) in advanced GBC also remains uncertain as the available phase II trials conducted in advanced biliary tract cancer included few patients with gallbladder primary tumors [85-87]. (See "Systemic therapy for advanced unresectable and metastatic cholangiocarcinoma", section on 'Antiangiogenic therapy'.)

SPECIAL CONSIDERATIONS

Is there a role for neoadjuvant therapy? — Most patients with advanced unresectable but nonmetastatic GBC are treated with systemic therapy only. Select patients who respond to initial systemic therapy may be interested in the chances of successfully receiving further local therapy for curative intent, such as chemoradiation (CRT) and surgery. However, there is insufficient high-quality evidence to support the routine use of neoadjuvant chemotherapy or CRT in advanced GBC. In addition, very few tumors have enough of a treatment response to CRT to be rendered subsequently resectable with curative intent. Patients who respond to systemic therapy and desire further local therapy should be carefully evaluated in a multidisciplinary fashion and encouraged to participate in clinical trials. (See "Surgical management of gallbladder cancer", section on 'Treatment for unresectable disease'.)

There are limited high-quality data on CRT for advanced unresectable GBC. Retrospective studies contain few patients with GBCs relative to extrahepatic cholangiocarcinomas and are heterogeneous in the treatment techniques and radiation therapy (RT) dose used [88-91]. Furthermore, although most observational studies in locally advanced, nonmetastatic GBC suggest that the integration of RT or CRT is associated with survival benefit [88,92-97], there are no randomized trials to confirm this approach.

Some patients may be rendered potentially resectable after neoadjuvant chemotherapy and/or CRT, but the frequency with which this occurs is unclear, and few data are available on long-term outcomes [98-105]. A systematic review concluded that there was insufficient evidence to support the routine use of neoadjuvant chemotherapy or CRT in advanced GBC [106].

If administered, CRT protocols for locally advanced unresectable GBC without distant metastases are extrapolated from studies in pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma. GBC mainly demonstrates locoregional progression [88], although it has a higher propensity for distant metastases than extrahepatic cholangiocarcinoma [107]. Patients typically receive concurrent fluoropyrimidine-based CRT. Tumor control is rarely achieved with RT alone in part because of the proximity of dose-limiting normal tissue that limits the potential to deliver an effective tumoricidal dose. (See "Treatment of locally advanced unresectable nonmetastatic cholangiocarcinoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Gallbladder cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – Gallbladder cancer (GBC) is an uncommon malignancy with a poor prognosis. Most patients with advanced unresectable or metastatic disease are treated with systemic therapy. Treatment goals are palliative, including relief of cancer-related symptoms (such as pain, jaundice, and bowel obstruction) and prolongation of life. (See 'Introduction' above.)

●Interventions for obstructive jaundice – For patients with obstructive jaundice, endoscopic or percutaneous biliary stenting is generally preferred at most institutions, if appropriate expertise is available. Such interventions may improve total bilirubin levels, which in turn could allow patients to initiate appropriate systemic therapy with agents that require hepatic metabolism. (See 'Interventions for obstructive jaundice' above.)

●Initial systemic therapy – The approach to systemic therapy for advanced or metastatic GBC is evolving. We encourage enrollment in clinical trials, where available. Our approach to initial therapy is based on patient performance status and bilirubin levels.

•Good performance status and no hyperbilirubinemia – For most patients with an Eastern Cooperative Oncology Group performance status less than 2 (table 1) and no hyperbilirubinemia, we suggest the addition of immunotherapy (either durvalumab or pembrolizumab) to gemcitabine plus cisplatin (table 2) for initial treatment (Grade 2B), as these chemoimmunotherapy regimens improved overall survival (OS) and demonstrated durable responses in randomized trials. (See 'Good performance status and no hyperbilirubinemia' above.)

-Although either chemoimmunotherapy regimen is appropriate, gemcitabine plus cisplatin and durvalumab has the advantage of a simpler maintenance therapy with single-agent durvalumab. (See 'Gemcitabine plus cisplatin and durvalumab' above and 'Gemcitabine plus cisplatin and pembrolizumab' above.)

-For patients who decline chemoimmunotherapy or are anticipated to not tolerate its toxicities, gemcitabine plus cisplatin (table 2) is an appropriate alternative. (See 'Gemcitabine plus cisplatin' above.)

-Other options for initial therapy include gemcitabine plus oxaliplatin (table 3 and table 4), gemcitabine plus capecitabine (table 5), gemcitabine plus carboplatin, gemcitabine plus fluorouracil (FU) and leucovorin (LV), and gemcitabine plus S-1 (where available). (See 'Other regimens' above.)

•Good performance status, persistent hyperbilirubinemia – For patients with good performance status and persistent hyperbilirubinemia despite stenting, the combination of a fluoropyrimidine plus oxaliplatin (eg, capecitabine plus oxaliplatin [CAPOX] (table 7) or oxaliplatin plus LV and short term-infusional FU [FOLFOX] (table 8)) is a reasonable alternative to a gemcitabine-based regimen. (See 'Good performance status and persistent biliary obstruction' above.)

•Borderline performance status or extensive comorbidities – For patients with a borderline performance status/extensive comorbidity, we suggest gemcitabine monotherapy (table 9) (Grade 2C). Other alternatives are capecitabine monotherapy, FU plus LV (table 6), or biweekly cisplatin plus gemcitabine. Supportive care alone is also an appropriate alternative. (See 'Borderline performance status' above.)

●Second-line therapy

•Patients with metastatic GBC should be tested for mismatch repair deficiency (dMMR)/microsatellite instability (MSI), high tumor mutational burden (TMB-H), and other actionable molecular alterations. Those who progress on initial systemic therapy and have an actionable molecular alteration may be candidates for second- and later-line treatment with immunotherapy or molecularly targeted therapy. (See 'Actionable molecular alterations' above.)

•In the absence of a specific actionable molecular alteration, for most patients who retain a good performance status and who had disease progression on a regimen that contains gemcitabine plus cisplatin, we suggest FOLFOX (table 8) rather than other systemic regimens (Grade 2B). (See 'No actionable molecular alterations' above.)

Other regimens with defined activity in the second-line setting include a fluoropyrimidine alone, irinotecan alone, CAPOX (table 7), or, if a non-gemcitabine-based regimen was used initially, gemcitabine plus capecitabine (table 5). (See 'Second-line therapy' above and "Treatment protocols for hepatobiliary cancer".)

•For patients with treatment-refractory metastatic GBC who do not have dMMR/MSI-H or high-levels of TMB, have been treated with all available standard therapies, and did not previously receive immunotherapy, options include either nivolumab plus ipilimumab or single-agent nivolumab. (See 'Biomarker-unselected patients' above.)

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  96. Todoroki T. Radiation therapy for primary gallbladder cancer. Hepatogastroenterology 1997; 44:1229.
  97. Paluri RK, Haris H, Li P, et al. Role of chemoradiation in gallbladder cancer-a single institution retrospective analysis. J Gastrointest Oncol 2023; 14:2212.
  98. Engineer R, Goel M, Chopra S, et al. Neoadjuvant Chemoradiation Followed by Surgery for Locally Advanced Gallbladder Cancers: A New Paradigm. Ann Surg Oncol 2016; 23:3009.
  99. de Aretxabala X, Losada H, Mora J, et al. [Neoadjuvant chemoradiotherapy in gallbladder cancer]. Rev Med Chil 2004; 132:51.
  100. Morganti AG, Trodella L, Valentini V, et al. Combined modality treatment in unresectable extrahepatic biliary carcinoma. Int J Radiat Oncol Biol Phys 2000; 46:913.
  101. Engineer R, Wadasadawala T, Mehta S, et al. Chemoradiation for unresectable gall bladder cancer: time to review historic nihilism? J Gastrointest Cancer 2011; 42:222.
  102. Chaudhari VA, Ostwal V, Patkar S, et al. Outcome of neoadjuvant chemotherapy in "locally advanced/borderline resectable" gallbladder cancer: the need to define indications. HPB (Oxford) 2018; 20:841.
  103. Creasy JM, Goldman DA, Dudeja V, et al. Systemic Chemotherapy Combined with Resection for Locally Advanced Gallbladder Carcinoma: Surgical and Survival Outcomes. J Am Coll Surg 2017; 224:906.
  104. Agrawal S, Mohan L, Mourya C, et al. Radiological Downstaging with Neoadjuvant Therapy in Unresectable Gall Bladder Cancer Cases. Asian Pac J Cancer Prev 2016; 17:2137.
  105. Kato A, Shimizu H, Ohtsuka M, et al. Surgical resection after downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer: a retrospective single-center study. Ann Surg Oncol 2013; 20:318.
  106. Hakeem AR, Papoulas M, Menon KV. The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer - A systematic review. Eur J Surg Oncol 2019; 45:83.
  107. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer 2003; 98:1689.
Topic 2499 Version 61.0

References

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2 : The role of dual-phase helical CT in assessing resectability of carcinoma of the gallbladder.

3 : Intrahepatic segment III cholangiojejunostomy in advanced carcinoma of the gallbladder.

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5 : Percutaneous self-expanding metal stents versus endoscopic polyethylene endoprostheses for treating malignant biliary obstruction: randomized clinical trial.

6 : Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice.

7 : Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer.

8 : Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma.

9 : Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer.

10 : Gallbladder cancer, a different disease that needs individual trials.

11 : Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer.

12 : Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

13 : Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

14 : Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial.

15 : Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.

16 : Quality of life, long-term survivors and long-term outcome from the ABC-02 study.

17 : Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study.

18 : Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder.

19 : Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer.

20 : Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study.

21 : Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study.

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28 : Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer.

29 : A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: a single-institution prospective study.

30 : A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202.

31 : A phase II study of gemcitabine and carboplatin combination chemotherapy in gallbladder carcinoma.

32 : Factors for hematopoietic toxicity of carboplatin: refining the targeting of carboplatin systemic exposure.

33 : Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study.

34 : Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial.

35 : Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

36 : Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract adenocarcinoma.

37 : Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial.

38 : Combined gemcitabine and S-1 chemotherapy for treating unresectable hilar cholangiocarcinoma: a randomized open-label clinical trial.

39 : Randomized phase II study of gemcitabine plus S-1 versus S-1 in advanced biliary tract cancer: a Japan Clinical Oncology Group trial (JCOG 0805).

40 : Gemcitabine plus cisplatin versus chemoradiotherapy in locally advanced biliary tract cancer: Fédération Francophone de Cancérologie Digestive 9902 phase II randomised study.

41 : A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study.

42 : Gemcitabine-based chemotherapy for advanced biliary tract carcinomas.

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44 : Epirubicin-sequential methotrexate-5-fluorouracil-leucovorin treatment in advanced cancer of the extrahepatic biliary system. A phase II study.

45 : 5-Fluorouracil, mitomycin, and doxorubicin (FAM) in carcinoma of the biliary tract.

46 : Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas.

47 : Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin.

48 : A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma.

49 : Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas.

50 : Weekly 24 h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract carcinomas.

51 : Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours.

52 : Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial.

53 : FOLFOX-4 as second-line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patients.

54 : Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial.

55 : Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer.

56 : Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer.

57 : A phase II study of gemcitabine in gallbladder carcinoma.

58 : Treatment efficacy/safety and prognostic factors in patients with advanced biliary tract cancer receiving gemcitabine monotherapy: an analysis of 100 cases.

59 : Biweekly cisplatin and gemcitabine in patients with advanced biliary tract cancer.

60 : Second-line chemotherapy in advanced biliary cancer: a systematic review.

61 : Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.

62 : Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues.

63 : Efficacy of Capecitabine Plus Irinotecan vs Irinotecan Monotherapy as Second-line Treatment in Patients With Advanced Gallbladder Cancer: A Multicenter Phase 2 Randomized Clinical Trial (GB-SELECT).

64 : A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin.

65 : Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study.

66 : Nanoliposomal irinotecan and fluorouracil plus leucovorin versus fluorouracil plus leucovorin in patients with cholangiocarcinoma and gallbladder carcinoma previously treated with gemcitabine-based therapies (AIO NALIRICC): a multicentre, open-label, randomised, phase 2 trial.

67 : Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion.

68 : Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency.

69 : Mutational spectrum and precision oncology for biliary tract carcinoma.

70 : Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.

71 : Patterns and genomic correlates of PD-L1 expression in patients with biliary tract cancers.

72 : Biliary cancer: Utility of next-generation sequencing for clinical management.

73 : Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets.

74 : Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and Combination: A Meta-regression Analysis.

75 : Prolonged Response to Anti-PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden.

76 : Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.

77 : Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial.

78 : SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

79 : A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer.

80 : The clinicopathologic significance of the expression of vascular endothelial growth factor-C in intrahepatic cholangiocarcinoma.

81 : Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study.

82 : A Multicenter Phase II Study of Gemcitabine, Capecitabine, and Bevacizumab for Locally Advanced or Metastatic Biliary Tract Cancer.

83 : Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers.

84 : Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study.

85 : Phase II Study of Ramucirumab in Advanced Biliary Tract Cancer Previously Treated By Gemcitabine-Based Chemotherapy.

86 : A multi-institutional phase 2 trial of regorafenib in refractory advanced biliary tract cancer.

87 : Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial.

88 : External-beam radiotherapy for localized extrahepatic cholangiocarcinoma.

89 : External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma.

90 : Radiation therapy for primary carcinoma of the extrahepatic biliary system. An analysis of 63 cases.

91 : Irradiation therapy for gallbladder carcinoma: recent advances.

92 : Residual, recurrent, or unresectable gastrointestinal cancer. Role of radiation in single or combined modality treatment.

93 : Trimodality therapy for advanced gallbladder cancer.

94 : Primary carcinoma of the gallbladder: role of external beam radiation therapy in patients with locally advanced tumor.

95 : Gallbladder carcinoma: role of radiation therapy.

96 : Radiation therapy for primary gallbladder cancer.

97 : Role of chemoradiation in gallbladder cancer-a single institution retrospective analysis.

98 : Neoadjuvant Chemoradiation Followed by Surgery for Locally Advanced Gallbladder Cancers: A New Paradigm.

99 : [Neoadjuvant chemoradiotherapy in gallbladder cancer].

100 : Combined modality treatment in unresectable extrahepatic biliary carcinoma.

101 : Chemoradiation for unresectable gall bladder cancer: time to review historic nihilism?

102 : Outcome of neoadjuvant chemotherapy in "locally advanced/borderline resectable" gallbladder cancer: the need to define indications.

103 : Systemic Chemotherapy Combined with Resection for Locally Advanced Gallbladder Carcinoma: Surgical and Survival Outcomes.

104 : Radiological Downstaging with Neoadjuvant Therapy in Unresectable Gall Bladder Cancer Cases.

105 : Surgical resection after downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer: a retrospective single-center study.

106 : The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer - A systematic review.

107 : Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies.