Treatment of advanced, unresectable gallbladder cancer

INTRODUCTION — Gallbladder cancer (GBC) is an uncommon but highly fatal malignancy; fewer than 5000 new cases are diagnosed each year in the United States. The majority are found incidentally in patients undergoing exploration for cholelithiasis; a tumor will be found in 1 to 2 percent of such cases [1,2]. The poor prognosis 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.

Surgery is the only potentially curative modality for patients with GBC. However, only a minority of patients are eligible for curative-intent surgery because of disease extent (either locoregionally advanced and unresectable because of local invasion into critical structures or metastasized beyond locoregional confines). For the remainder, treatment is palliative in nature. (See "Prognosis and adjuvant treatment for localized, resected gallbladder cancer".)

The goals of palliation for advanced GBC (as for other pancreaticobiliary cancers) are relief of pain, jaundice, and bowel obstruction, and prolongation of life. Patients who have pain from local growth may benefit from radiation therapy with or without concomitant chemotherapy. Although a biliary or intestinal bypass can be considered, percutaneous or endoscopic approaches are generally preferred given the limited median survival in patients with advanced disease (generally less than six months).

Here we will discuss the treatment of advanced, unresectable GBC. The epidemiology, risk factors, clinical features, and diagnostic evaluation of GBC and treatment for localized, potentially resectable disease are covered separately, as is treatment for advanced bile duct cancer (cholangiocarcinoma). (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis" and "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma" and "Systemic therapy for advanced cholangiocarcinoma".)

ISSUES SPECIFIC TO PATIENTS WITH OBSTRUCTIVE JAUNDICE — Although a biliary or intestinal bypass can be considered for palliation of obstructive jaundice, stenting via an endoscopic or percutaneous approach is generally preferred given that the majority of such patients will have disseminated, incurable disease and that there is limited median survival in patients with advanced disease (generally less than six months). At most institutions, an initial endoscopic attempt at drainage is usually preferred, as long as local endoscopic expertise is available.

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 [3]. Preoperative jaundice is considered to be 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 [4]. (See "Surgical management of gallbladder cancer", section on 'Unresectable disease'.)

Although biliary or intestinal bypass can successfully palliate obstructive jaundice [5], 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 [6]. 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 [7,8]. 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".)

LOCAL TREATMENT FOR LOCALLY ADVANCED NON-METASTATIC DISEASE — Due to the rarity of GBC, management protocols for nonresectable disease are commonly extrapolated from studies of tumors of the pancreas or bile ducts (cholangiocarcinoma). Similar to these two entities, progression of GBC is mainly locoregional, although GBC has a higher propensity for distant involvement than does cholangiocarcinoma [9]. In spite of this, the two tumors are generally managed similarly with external beam radiation therapy (RT) when they are locoregionally advanced and unresectable, particularly if the patient is symptomatic. Tumor control is rarely achieved with RT alone, and we suggest that most patients receive concurrent fluoropyrimidine-based chemoradiotherapy. (See "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma".)

There are very few data on the outcome of primary RT for unresectable GBC. Published retrospective series are small, contain small numbers of GBCs relative to extrahepatic cholangiocarcinomas, and are heterogeneous with regard to treatment technique and RT dose [10-13]. The available data suggest that 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.

Most patients with locally advanced, unresectable disease receive a combination of chemotherapy and RT to take advantage of the radiation-sensitizing properties of certain chemotherapeutic agents, although there are few data validating this approach [10,14]. With or without chemotherapy, the first site of failure in patients with a margin-positive resection is usually locoregional [10]. Furthermore, whether the use of chemoradiotherapy (or even RT alone) favorably impacts survival in the setting of locally advanced, non-metastatic disease continues to be debated [10,15-18].

Despite uncertainty as to benefit, chemoradiotherapy is an acceptable choice for locoregional therapy of a locally advanced, unresectable GBC. As with locally advanced, unresectable cholangiocarcinoma, infusional fluorouracil delivered during a course of external beam RT is the most commonly used approach. (See "Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma".)

Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest either concomitant fluoropyrimidine-based chemoradiotherapy or palliative chemotherapy for patients with locally advanced, unresectable GBC [4]. On the other hand, consensus-based guidelines from the European Society for Medical Oncology (ESMO) suggest systemic chemotherapy in this setting; RT may be considered in patients with localized disease after first-line chemotherapy [19]. Patients should be encouraged to participate in clinical trials.

Some patients may be rendered potentially resectable after chemoradiotherapy, but the frequency with which this occurs is unclear, and few data are available on long-term outcomes after neoadjuvant chemotherapy or chemoradiotherapy [20-27]. A systematic review concluded that there was insufficient evidence to support the routine use of neoadjuvant therapy in advanced GBC [28].

PALLIATIVE SYSTEMIC CHEMOTHERAPY — Systemic chemotherapy provides modest benefit in the treatment of advanced GBC. Most published series are small and consist of a heterogeneous population of patients with GBC, cholangiocarcinoma, and occasionally some pancreatic and hepatic cancers that tend to respond differently to systemic therapy [29-32].

Reported objective response rates with chemotherapy in patients with GBC include a range of 10 to 60 percent. There are only limited data evaluating the impact of treatment on survival. The only randomized trial compared best supportive care versus chemotherapy with fluorouracil (FU) plus leucovorin (LV) or gemcitabine plus oxaliplatin (GEMOX) in 81 patients with unresectable GBC. Median overall survival was 4.5, 4.6, and 9.5 months in the basic supportive care, FU/LV, and GEMOX groups, respectively [33].

All of the studies described below were conducted in patients with adenocarcinoma, which is the most common histology of GBC. There are no available data that are specific to the treatment of advanced adenosquamous or squamous cell GBCs, and these patients are typically managed similarly. Treatment of patients with advanced small cell carcinoma of the gallbladder is discussed elsewhere. (See "Extrapulmonary small cell cancer", section on 'Gallbladder ESCC'.)

First-line chemotherapy — For patients with locoregionally advanced, unresectable GBC and those with distant metastatic disease who are able to tolerate it, palliative chemotherapy is an appropriate option. The optimal regimen has not been defined by randomized trials, and no single chemotherapy agent or combination regimen can be recommended for all patients as a standard of care at present.

Good performance status and no or minimal hyperbilirubinemia — We prefer that patients enroll in clinical trials testing new agents or combinations whenever possible. Off protocol, the optimal first-line regimen is not established. We suggest a gemcitabine-based combination rather than gemcitabine monotherapy or a non-gemcitabine-based regimen for most patients with a good performance status who can tolerate chemotherapy and who do not have significant hyperbilirubinemia. (See 'Gemcitabine-based combinations' below.)

Appropriate options include (see "Treatment protocols for hepatobiliary cancer"):

●Gemcitabine plus cisplatin (gem/cis (table 1)). (See 'Gemcitabine plus cisplatin' below.)

●Gem/cis and durvalumab.

●Gemcitabine plus capecitabine (table 2) or gemcitabine plus S-1 (where available). (See 'Gemcitabine plus S-1' below and 'Gemcitabine plus capecitabine' below.)

●GEMOX (table 3 and table 4). (See 'Gemcitabine plus oxaliplatin' below.)

The following represents our approach:

Gemcitabine-based combinations

Gemcitabine plus cisplatin — The combination of gem/cis (table 1) is a standard option for treatment of advanced GBC, especially for patients without hyperbilirubinemia [34-37].

The superiority of gem/cis over gemcitabine alone was shown in the multicenter ABC-02 trial, in which 410 patients with locally advanced (25 percent) or metastatic bile duct (n = 242), gallbladder (n = 148), or ampullary (n = 20) cancer were randomly assigned to 24 weeks of cisplatin (25 mg/m²) followed by gemcitabine (1000 mg/m²) on days 1 and 8 every 21 days or to gemcitabine alone (1000 mg/m² on days 1, 8, and 15 every 28 days) [37].

At a median follow-up of 8.2 months, median overall survival was significantly greater with gem/cis (11.7 versus 8.1 months), as was median progression-free survival (8 versus 5 months). Toxicity was roughly comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gem/cis (25 versus 17 percent) and of grade 3 or 4 abnormal liver function with gemcitabine alone (27 versus 17 percent). Most quality of life scales showed a trend favoring combined therapy, although the differences were not statistically significant [38]. Furthermore, of the 21 long-term (>3 years) survivors, 14 had received combination therapy.

The authors concluded that gem/cis should be considered the reference regimen for advanced biliary cancer. However, few trials have directly compared this combination with other gemcitabine combinations (eg, with capecitabine or LV-modulated FU) or capecitabine plus oxaliplatin (CAPOX) in randomized trials. A single randomized trial comparing gem/cis with GEMOX found no significant difference in outcomes, but a trend toward better survival with gemcitabine/oxaliplatin. (See 'Gemcitabine plus oxaliplatin' below.)

Furthermore, the available evidence from randomized trials is insufficient to prove whether or not a gemcitabine-containing combination, such as gem/cis, is better than a non-gemcitabine-containing combination. (See 'Non-gemcitabine-based regimens' below.)

Durvalumab plus gemcitabine and cisplatin — For patients in whom the cost of therapy is not an issue, durvalumab plus gem/cis is a is a reasonable alternative to gem/cis and may be preferred by some patents for first-line therapy. Although the benefits of adding durvalumab to gem/cis are relatively modest and adding the third drug greatly contributes to the cost of therapy, the long-term survival benefits are potentially clinically meaningful for some patients. Unfortunately, there are no predictive biomarkers to select patients who may benefit.

The superiority of adding the immune checkpoint inhibitor durvalumab to gem/cis versus gem/cis alone was shown in the TOPAZ-1 trial [39]. Patients with previously untreated unresectable locally advanced or metastatic intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer (n = 685) were randomly assigned to durvalumab (1500 mg every three weeks) or placebo plus gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) on days 1 and 8 every three weeks for up to eight cycles, followed by durvalumab (1500 mg every four weeks) or placebo until disease progression or unacceptable toxicity. Durvalumab-containing therapy significantly improved overall survival, the primary endpoint (median 12.8 versus 11.5 months, HR 0.8, 95% CI 0.66-0.97), and more than twice as many individuals were still alive at 24 months (24.9 versus 10.4 percent). The addition of durvalumab was also associated with longer progression-free survival and a higher objective response rate (26.7 versus 18.7 percent). Durvalumab did not add additional toxicity that was observed with gem/cis, and only 13 percent of patients developed immune-mediated side effects; 2.4 percent were grade 3 or 4. (See "Toxicities associated with immune checkpoint inhibitors".)

Largely based on these results, the US Food and Drug Administration (FDA) has approved durvalumab, in combination with gemcitabine and cisplatin, for adult patients with locally advanced or metastatic biliary tract cancers [40].

Gemcitabine plus S-1 — S-1 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, which is thought responsible for treatment-related diarrhea). It is available in some countries outside of the United States.

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) was directly compared with the same dose and schedule of gem/cis (25 mg/m² intravenously on days 1 and 8) in the Japanese phase III FUGA-BT trial [41]. A total of 354 patients with chemotherapy-naive recurrent or unresectable adenocarcinoma of the gallbladder, biliary tract, or ampulla of Vater were randomized, and the trial was designed to demonstrate noninferiority. In a preliminary report presented at the 2018 ASCO Gastrointestinal Cancers Symposium, gemcitabine plus S-1 was noninferior in terms of median overall survival (15.1 versus 13.4 months, hazard ratio 0.95, 95% CI 0.78-1.15), median progression-free survival (6.8 versus 5.8 months), and objective response rate (30 versus 32 percent). Both treatments were generally well tolerated, although clinically relevant adverse effects (grade 2 or worse fatigue, anorexia, nausea, vomiting, mucositis, and diarrhea) were slightly more frequent with gem/cis (35 versus 31 percent).

Gemcitabine plus fluorouracil and leucovorin — Whether adding treatment with FU and 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) [42]. 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 overall survival were 5.2 and 7.2 months, respectively [43].

Gemcitabine plus capecitabine — The combination of gemcitabine plus the oral FU prodrug capecitabine (table 2) seems to be associated with higher response rates than gemcitabine plus FU for advanced biliary tumors [44-48], and at least three phase II trials report a median survival of 13 to 16 months [45,47,48]:

●In a study of 75 patients (27 with GBC, 3 with ampulla of Vater cancer, and the remainder with cholangiocarcinoma), gemcitabine (1000 mg/m² on days 1 and 8) plus capecitabine (650 mg/m² twice daily for 14 days of every 21-day cycle) was well tolerated [47]. There were 22 objective responses (three complete), which were seen in both tumor types. The median progression-free and overall survival durations were 6.2 and 12.7 months, respectively.

●Two smaller phase II trials of the same combination in 22 and 12 patients with GBC, respectively, reported objective responses in 6 of 22 (28 percent) and 2 of 12 (17 percent); the median survival duration was 14 months in both trials [44,48].

●In another report of 24 patients with GBC treated with the same dose of gemcitabine but a higher capecitabine dose (1000 mg/m² twice daily for 14 of every 21 days), one-third had a partial response, and median survival was 16 months [45].

Not all studies suggest prolongation of survival with this combination, however [44,46]:

●The Southwest Oncology Group (SWOG) studied gemcitabine (1000 mg/m² over 100 minutes on days 1 and 8) plus capecitabine (650 mg/m² twice daily for 14 of every 21 days) in 57 patients with unresectable or metastatic GBC (n = 17) or cholangiocarcinoma (n = 35) [49]. There were seven partial responses (response rate 13 percent), and 12 (23 percent) had stable disease as the best response. Treatment was reasonably well tolerated, with only four patients developing grade 4 neutropenia. Median survival was seven months.

●In a second study of combined therapy in 45 patients (22 with GBC, the remainder with cholangiocarcinoma), the median survival duration for the entire group was 14 months, but according to tumor type, it was 19 months for cholangiocarcinoma and only 6.6 months for GBC.

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 [50]) studies [51-54]. 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 upper limit of normal (ULN). The response rate was 36 percent, and median overall survival duration was 14.3 months using every-other-week gemcitabine (1000 mg/m² on day 1) and oxaliplatin (100 mg/m² on day 2) [51]. 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 overall survival was similar in both groups (10.4 versus 10.6 months), as was the six-month progression-free survival rate (45 versus 47 percent) [54]. 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 [55]. At a median follow-up of 10.5 months, the objective response rates were no different (23 versus 24 percent), and median overall survival 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 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 [56]. Median overall survival 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 [57].

Issues specific to the dosing of carboplatin are discussed in detail elsewhere. (See "Dosing of anticancer agents in adults", section on 'Carboplatin'.)

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 chemoradiotherapy for first-line therapy of advanced biliary tract cancer [58-63]. 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 [64]. Additional randomized trials are needed with gem/cis as the control arm.

Some newer data suggest potential benefit from more aggressive combination chemotherapy regimens such as oxaliplatin, irinotecan, leucovorin plus short-term infusional fluorouracil (FOLFIRINOX), but the higher than expected response rates have also been accompanied by significant toxicity, especially involving the gastrointestinal tract [65]. 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.

Patients with biliary obstruction — For patients with persistent hyperbilirubinemia despite stenting, we prefer a non-gemcitabine-based regimen, such as LV-modulated FU (table 5) or a fluoropyrimidine plus oxaliplatin combination.

In past 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 [66-68]. Many, but not all, more recent 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) [69-73].

Fluoropyrimidine plus oxaliplatin — One active non-gemcitabine-containing regimen is CAPOX (table 6):

●In one trial, CAPOX was administered to 65 evaluable patients with biliary tract tumors, 27 with GBC, and the remainder with cholangiocarcinoma [74]. 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 overall survival was similar in both groups (10.4 versus 10.6 months), as was the six-month progression-free survival rate (45 versus 47 percent) [54]. 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 7) [75]. (See 'Second-line chemotherapy' 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 [69]. 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) [73]. 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 overall survival 9 versus 12 months, respectively) [76]. ECF was associated with significantly less acute toxicity.

Borderline performance status — For patients with a borderline performance status, we suggest gemcitabine as a single agent (table 8). Other alternatives, especially for patients with hyperbilirubinemia, are capecitabine monotherapy or LV-modulated FU (table 5). 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 [31,77-79]. 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 [30]. 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 [80], or LV-modulated FU (table 5) [71,72]. (See 'Gemcitabine plus cisplatin' above.)

Second-line chemotherapy — There are few prospective trials comparing specific chemotherapy regimens in the second-line setting for advanced biliary tract cancer, and the selection of candidates for second-line therapy as well as the optimal regimen are not established. We generally choose a second line regimen that does not overlap with the agents used first-line. For most patients who have disease progression while receiving gem/cis and who retain an adequate performance status, we suggest FOLFOX (table 7). Other options for second-line treatment include immunotherapy using an immune checkpoint inhibitor, a fluoropyrimidine alone, irinotecan alone, or CAPOX (table 6), or if a non-gemcitabine-containing regimen was used initially, gemcitabine plus capecitabine (table 2).

Benefit of second-line therapy — The randomized ABC-06 trial directly compared FOLFOX (table 7) chemotherapy versus active symptom control in 162 patients with disease progression after prior cisplatin/gemcitabine; this included 117 patients with cholangiocarcinoma, 34 with GBC, and 11 with ampullary cancer [81]. FOLFOX was associated with significantly better rates of overall survival at 6 (51 versus 36 percent) and 12 months (26 versus 11 percent), and significantly, albeit modestly, improved median overall survival (6.2 versus 5.3 months, HR 0.69, 95% CI 0.50-0.97). Grade 3 or 4 toxic events were reported in 59 percent of the group receiving FOLFOX (versus 37 percent of those undergoing symptom control alone), with fatigue and neutropenia being more frequent in the FOLFOX arm. Notably, the protocol allowed for an initial 20 percent reduction in fluorouracil dose for individuals older than 70, and a reduced initial oxaliplatin dose (65 rather than 85 mg/m²) if the creatinine clearance was 30 to 60 mL/min.

Choice of regimen — For most patients who have disease progression following first-line gem/cis and retain a good performance status, we suggest FOLFOX based upon data from the ABC-06 trial, discussed above. Another acceptable alternative is liposomal irinotecan plus leucovorin-modulated FU, or immunotherapy.

Regimens with defined activity in the second-line setting include FOLFOX (table 7), as was used in the ABC-06 trial, described above; liposomal irinotecan plus leucovorin-modulated FU (table 9) as was used in the randomized phase II NIFTY trial, described below; gemcitabine plus capecitabine (table 2); a fluoropyrimidine alone; irinotecan alone [82]; or CAPOX (if cisplatin was used as first-line therapy (table 6)) [75,81,83-85].

A benefit for second-line liposomal irinotecan (70 mg/m² every 90 minutes) in combination with leucovorin [LV]-modulated short-term infusional FU compared with FU/LV alone after progression on gem/cis was addressed in the randomized phase II NIFTY trial [85]. In a preliminary report presented at the 2021 annual ASCO meeting, of the 174 patients who were assessable for response (53 with GBC) median progression-free survival (the primary endpoint, as assessed by blinded independent central review) was significantly better in the irinotecan group (7.1 versus 1.4 months) as was median overall survival (8.6 versus 5.5 months) and objective response rate (15 versus 6 percent). The most common grade 3 or worse adverse events in the irinotecan group were neutropenia, fatigue, and nausea.

Another option is immunotherapy. Patients with deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) tumors or high levels of tumor mutational burden (TMB) can be offered pembrolizumab, patients with overexpression of PD-L1 could be offered a trial of nivolumab, and others can be considered for nivolumab plus ipilimumab based on the phase II CAA209-538 trial, and the lack of biomarker data. We would not offer immune checkpoint inhibitor therapy for second-line therapy if durvalumab was administered first-line. (See 'Durvalumab plus gemcitabine and cisplatin' above.)

Selecting candidates for second-line therapy — The optimal selection of candidates for second-line chemotherapy is not established [86]. Two independent studies suggest that patients who have a good performance status (0 or 1 (table 10)), had disease control with first-line chemotherapy, 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 [87,88], but whether these characteristics predict chemotherapy responsiveness or more favorable biologic behavior is not clear.

Molecularly targeted therapy — Targeted testing of advanced GBCs for dMMR/MSI and for specific molecular alterations for which a targeted treatment might be available is indicated for those who might be eligible for molecularly targeted therapy or immunotherapy, preferably within the context of a clinical trial.

Next-generation sequencing to identify actionable molecular abnormalities — 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 [89]. 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. Two such gene panel tests (MSK-IMPACT [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling Actionable Cancer Targets] and F1CDx [FoundationOne CDx]) are US FDA-approved in the United States. 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 free DNA (cfDNA) may be used [89]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management'.)

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, deficient mismatch repair (dMMR)/high levels of tumor mutational burden (TMB), and mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2. Notably, alterations in FGFR and IDH are more likely in intrahepatic cholangiocarcinomas than in GBC, while HER2 overexpression may be found more commonly with GBC than with cholangiocarcinomas. Available data on molecularly targeted therapy for advanced biliary tract cancers (including GBC) with specific targetable genomic alterations such as these are presented in more detail separately. Specific information on immunotherapy for advanced GBC is presented below. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'Next-generation sequencing to identify actionable molecular abnormalities'.)

Immunotherapy — Immunotherapeutic approaches to cancer therapy are based upon the premise that the immune system plays a key role in the surveillance and eradication of malignancy and that tumors evolve ways to elude the immune system. Programmed cell death 1 (PD-1) is a key immune checkpoint receptor that is expressed by activated T-cells. PD-1 binds to its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed on tumor cells, thereby causing immunosuppression and preventing the immune system from rejecting the tumor.

Biomarker-selected patients

●Deficient mismatch repair/high levels of tumor mutational burden – Tumors that lack the mismatch repair mechanism (ie, dMMR) harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such mismatch repair defects, and the neoantigens generated from mutations such as these have the potential to be recognized as "non-self" immunogenic antigens. The biologic footprint of dMMR tumors is MSI-H. In fact, patients with a wide variety of tumors that are MSI-H or dMMR (but not those with proficient mismatch repair tumors) experience clinical benefit from inhibitors of PD-1, and some responses are durable. In addition, some tumors that are not dMMR have high levels of TMB (>10 mutations per megabase [mut/Mb]). The frequency of dMMR or MSI-H is approximately 5 percent for GBC [90], and approximately 4 percent of biliary tract cancers have high levels of TMB, with frequency being highest for GBC [91].

In May 2017, the FDA approved pembrolizumab for treatment of a variety of advanced solid tumors, including GBC, that were MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options. In June 2020, the FDA also approved pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that are tissue TMB-high (≥10 mut/Mb) by an FDA-approved assay, who have progressed following prior therapy, and who have no satisfactory alternative treatment options. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

We would not typically offer second-line immunotherapy to individuals who received frontline durvalumab. (See 'Durvalumab plus gemcitabine and cisplatin' above.)

●PD-L1 overexpression – Other biomarkers such as overexpression of the programmed cell death 1 ligand 1 (PD-L1) may also predict response to immune checkpoint inhibitor therapy in biliary tract cancers, including GBC [92]. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'Immunotherapy'.)

Biomarker-unselected patients — Emerging data also suggest that durable responses to immunotherapy are possible in patients with advanced GBC who are unselected for biomarker status. The multicenter open-label phase II CAA209-538 clinical trial of nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) every three weeks for four doses followed by nivolumab (3 mg/kg) every two weeks for advanced rare cancers included 39 patients with biliary tract cancers, of whom 13 had GBC; enrolled patients were unselected for biomarker expression, and 33 had previously received one or more lines of systemic therapy for advanced disease [93]. In this subgroup, there were four objective responses, with all responding patients being treated in the second-line setting. All responders had proficient mismatch repair tumors, but PD-L1 overexpression status as a predictive marker was not addressed. Five other patients had stable disease for a disease control rate of 70 percent in this group. Duration of response ranged from 2.5 to >23 months. In the entire group of 39 patients with biliary tract cancer, approximately one-half experienced an immune-related adverse event of any grade, and ≥grade 3 toxic effects occurred in six (15 percent).

These data are difficult to interpret in the absence of information on PD-L1 overexpression. However, given the relatively high response rate and durability of responses, until further information is available regarding the relevance of additional biomarkers on response rates to combined immunotherapy, based upon this study, a trial of nivolumab plus ipilimumab is reasonable in the setting of second-line therapy for patients with GBC who do not have dMMR, high levels of TMB, or PD-L1 overexpression, and who did not receive frontline durvalumab. (See 'Durvalumab plus gemcitabine and cisplatin' above.)

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 [94]. 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 [95-98], 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 [99-101].

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 5^th to 6^th 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 10^th to 12^th 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 palliative therapy for advanced unresectable tumors

•Gallbladder cancer (GBC) is an uncommon but commonly fatal malignancy. For patients who are not eligible for curative-intent surgery treatment is palliative in nature. The goals of palliation for advanced GBC (as for other pancreaticobiliary cancers) are relief of pain, jaundice, and bowel obstruction, and prolongation of life. (See 'Introduction' above.)

•Although a biliary or intestinal bypass can be considered for palliation of obstructive jaundice, stenting via an endoscopic or percutaneous approach is generally preferred given that the majority of such patients will have disseminated, incurable disease and that there is limited median survival in patients with advanced disease (generally less than six months). (See 'Issues specific to patients with obstructive jaundice' above.)

●Locoregional treatment for nonmetastatic disease

•Management protocols for locally advanced, unresectable, but non-metastatic GBC are commonly extrapolated from studies of tumors of the bile ducts (cholangiocarcinoma). Tumor control is rarely achieved with RT alone, and we suggest that most patients receive concurrent fluoropyrimidine-based chemoradiotherapy (Grade 2C). (See 'Local treatment for locally advanced non-metastatic disease' above.)

●Palliative chemotherapy

•For patients with locoregionally advanced, unresectable GBC and those with distant metastatic disease who are able to tolerate it, palliative chemotherapy is an appropriate option. The optimal regimen has not been defined by randomized trials, and no single chemotherapy agent or combination regimen can be recommended for all patients as a standard of care.

•We prefer clinical trial participation whenever possible. If trials are unavailable or patients are ineligible, we suggest a gemcitabine-based combination rather than gemcitabine monotherapy for most patients with a good performance status who can tolerate chemotherapy and who do not have significant hyperbilirubinemia (Grade 2B). We also suggest a gemcitabine-based combination over a non-gemcitabine-based regimen for most patients (Grade 2C). (See 'Gemcitabine-based combinations' above.)

Appropriate options include (see "Treatment protocols for hepatobiliary cancer"):

-Gemcitabine plus cisplatin and durvalumab. (See 'Durvalumab plus gemcitabine and cisplatin' above.)

-Gemcitabine plus cisplatin (table 1). (See 'Gemcitabine plus cisplatin' above.)

-Gemcitabine plus capecitabine (table 2) or gemcitabine plus S-1 (where available). (See 'Gemcitabine plus S-1' above and 'Gemcitabine plus capecitabine' above.)

-Gemcitabine plus oxaliplatin (GEMOX) (table 3 and table 4). (See 'Gemcitabine plus oxaliplatin' above.)

For patients with a serum bilirubin >1.6 mg/dL, the combination of a fluoropyrimidine plus oxaliplatin (eg, capecitabine plus oxaliplatin [CAPOX] (table 6) or oxaliplatin plus leucovorin [LV] and short term-infusional FU [FOLFOX] (table 7)) is a reasonable alternative to a gemcitabine-based regimen. (See 'Patients with biliary obstruction' above.)

•For patients with a borderline performance status/extensive comorbidity, we suggest gemcitabine monotherapy (table 8) (Grade 2C). Other alternatives are capecitabine monotherapy, LV-modulated FU (table 5), or biweekly cisplatin plus gemcitabine. Supportive care alone is also an appropriate alternative. (See 'Borderline performance status' above.)

●Second-line therapy

•No regimen can be considered standard after failure of an initial gemcitabine-based regimen. Targeted testing of advanced GBCs for mismatch repair deficiency (dMMR)/microsatellite instability (MSI), overexpression of PD-L1, and for other specific molecular alterations for which a targeted treatment might be available is indicated for those who might be eligible for molecularly targeted therapy or immunotherapy, preferably within the context of a clinical trial. (See 'Molecularly targeted therapy' above.)

•In the absence of a specific molecular alteration, for most patients who retain a good performance status and who had disease progression while receiving gemcitabine plus cisplatin regimen, we suggest FOLFOX (table 7) (Grade 2B). Another reasonable alternative is liposomal irinotecan plus leucovorin-modulated FU (table 9). (See 'Choice of regimen' above.)

Other regimens with defined activity in the second-line setting include a fluoropyrimidine alone, irinotecan alone, CAPOX (table 6), or, if a non-gemcitabine-based regimen was used initially, gemcitabine plus capecitabine (table 2). (See 'Second-line chemotherapy' above and "Treatment protocols for hepatobiliary cancer".)

Another option in this setting is immunotherapy, unless durvalumab was used in the first line. Eligible patients can be considered for nivolumab plus ipilimumab regardless of biomarker status based on the phase II CAA209-538 trial. (See 'Immunotherapy' above.)