Prognosis and adjuvant treatment for localized, resected 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. Most GBC is found incidentally in patients undergoing exploration for cholelithiasis; a tumor will be found in 1 to 2 percent of such cases [1-4].

Surgery is the only potentially curative therapy for GBC. However, even after complete resection, outcomes are poor, particularly for T3 and/or node-positive disease. High rates of both local and distant recurrence have prompted interest in adjuvant chemotherapy and radiation therapy. (See "Surgical management of gallbladder cancer", section on 'Outcomes'.)

A high percentage of GBCs are initially unsuspected and detected at the time of laparoscopic cholecystectomy for presumed cholecystitis. The next step for these patients (before adjuvant therapy) is additional surgery to remove lymph nodes and the segments of liver above the gallbladder. (See "Surgical management of gallbladder cancer", section on 'Gallbladder cancer diagnosed during gallbladder surgery'.)

This topic review will cover adjuvant treatment for localized, resected GBC. The epidemiology, risk factors, clinical features, and diagnostic evaluation, surgical treatment, and treatment for locally advanced unresectable and metastatic GBC are covered separately, as is adjuvant treatment after resection of cholangiocarcinoma. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis" and "Surgical management of gallbladder cancer" and "Treatment of advanced, unresectable gallbladder cancer" and "Adjuvant and neoadjuvant therapy for localized cholangiocarcinoma".)

PROGNOSIS AND PATTERNS OF SPREAD — GBC is an aggressive cancer; among resected patients, five-year overall survival rates are from 5 to 32 percent [5-12], although higher rates (45 to 50 percent) are reported in some contemporary reports of patients with incidentally found GBC after extended reresection [13,14]. The poor prognosis associated with most cases of GBC is related to the advanced stage at diagnosis, which is due both to the vagueness and nonspecificity of symptoms and the anatomic position of the gallbladder [15]. Locoregionally, GBC frequently extends directly to adjacent structures such as the liver, stomach, duodenum, pancreas, colon, omentum, or abdominal wall. Peritoneal carcinomatosis involving the upper abdomen may complicate the disease in patients with transmural or serosal penetration.

Recurrences develop in 35 to 67 percent of patients [6,7,13,16], and outcomes are significantly worse among those who recur [13].

The risk of recurrence is not constant over time, with up to two-thirds of all recurrences occurring in the first 12 months, and the majority of the remainder within 24 months. As a result, while overall survival usually decreases over time, the longer an individual has survived since treatment, the greater the chance of additional survival. This "conditional survival" may be a more accurate estimate of long-term survival:

●In one analysis of 1071 patients undergoing curative intent therapy for a GBC ≥T1b from 2000 to 2018 at multiple international centers, at a median follow-up of 24.5 months, five-year relapse-free survival (RFS) was 47 percent for the entire population, while it was 71 percent for those who were recurrence-free at 12 months, and 87 percent for those without recurrence at 24 months [17].

●In another report of 312 patients undergoing potentially curative surgical resection for GBC, with a median follow-up of 29 months, three-year overall survival was 41 percent for the entire cohort, but three-year conditional overall survival increased to 49 percent for those patients who were still alive at one year postsurgery, and to 62 percent among those who were still alive at two years [11].

These data might be used to inform the post-treatment-surveillance strategy. (See 'Post-treatment surveillance' below.)

Prognostic factors — The main prognostic factors are tumor invasion depth as indicated by the pathologic tumor (T) stage, lymph node metastases, serum levels of the tumor marker cancer antigen 19-9 (CA 19-9), status of the surgical margins, tumor grade, and presence of lymphovascular and perineural invasion [5,18-21].

T stage has a major impact on prognosis. The current (eighth) edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging criteria contains several changes to both T and nodal (N) staging compared with the earlier 2010 edition (table 1) [22]. The most important are the subdivision of T2 disease into two categories based upon whether the tumor has arisen on the peritoneal or the hepatic side of the gallbladder, and a change from location-based definitions to a number-based N category assessment. Observed survival rates from a multicenter series of 437 cases of gallbladder cancer (GBC), stratified according to stage using the eighth edition staging criteria, are depicted in the figure (figure 1) [23]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'TNM staging system'.)

The risk of both lymphatic and distant metastases increases as T stage increases. As an example, in one report of 410 patients presenting for therapy of GBC with or without a prior operation elsewhere, lymph node metastases were present in 33, 58, and 69 percent of those with T2, T3, or T4 primary tumors; the corresponding rates for peritoneal and/or liver metastases were 16, 42, and 79 percent, respectively [24]. An important point is that the T staging for GBC differs from that of other sites in the gastrointestinal tract; while a T2 designation at other sites, such as the colon, indicates invasion of the muscular layer, this is classified as T1b disease for GBC (table 1). (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'TNM staging system'.)

Patterns of disease recurrence — Following resection of GBC, disease recurrence can be locoregional, distant, or both. In contrast to patients who have margin-positive resections, in whom locoregional recurrences predominate, the pattern of disease recurrence following complete resection of GBC is predominantly distant [6,25,26], though locoregional recurrences also occur [27]:

●In a series of 97 patients undergoing surgery for GBC (90 percent of whom had a margin-negative resection), isolated locoregional disease as the first site of failure occurred in 15 percent of cases, while an initial recurrence involving a distant site, with or without concomitant locoregional recurrence, occurred in 85 percent [6].

●In another retrospective review of 166 patients undergoing surgical resection with curative intent for GBC, 53 had a tumor recurrence [7]. The main patterns of recurrence were:

•Retroperitoneal lymph nodes (28 percent)

•Intrahepatic (22 percent)

•Locoregional recurrence (hilum, bilioenteric anastomosis, hepatic resection margin; 20.9 percent)

•Peritoneum, lung, bone, and abdominal wall (totaling 15 percent)

•Other distant lymph nodes (14 percent)

ADJUVANT THERAPY

Indications — There is a paucity of high-quality evidence to support adjuvant treatment in gallbladder cancer (GBC), and patients should be encouraged to participate in clinical trials evaluating new strategies. One such trial, ACTICCA-1, is open to accrual in Europe, and eligible patients should be encouraged to enroll. If protocol participation is not available or is declined, we suggest adjuvant therapy for patients with completely resected muscle-invasive (≥T1b (table 1)), node-positive, or margin-positive GBC. Although guidelines from the American Society of Clinical Oncology (ASCO) suggest adjuvant therapy for all patients with resected GBC, we would not offer therapy to a patient with a resected T1a, node-negative tumor, given that these patients were not eligible for either the BILCAP or the Southwest Oncology Group (SWOG) trials. This approach is consistent with National Comprehensive Cancer Network (NCCN) guidelines.

Choice of regimen — There is no consensus as to the optimal adjuvant approach. Given the high rate of distant recurrence, especially after a complete resection, and the results of the phase III BILCAP trial, we prefer six months of postoperative chemotherapy alone with capecitabine monotherapy for most patients. If capecitabine is chosen, we would start treatment with no more than a 1500 mg total dose twice daily. An alternative approach combining concomitant fluoropyrimidine-based chemoradiotherapy with four months of systemic chemotherapy is also acceptable, particularly for patients with margin-positive disease. In this situation, the choice of chemotherapy can be either capecitabine monotherapy or capecitabine plus gemcitabine (eg, as was used in SWOG S0809 (table 2) [28]). For patients who receive both adjuvant chemoradiotherapy and chemotherapy, the optimal way to integrate chemoradiotherapy and chemotherapy is uncertain. In general, it is preferable to start with chemotherapy first, based on the rationale that this approach may avoid radiation therapy (RT) for patients who are destined to develop early distant metastases and will not benefit from it.

Benefits — There are few adequately powered randomized trials of adjuvant therapy to guide clinicians treating patients with GBC. The lack of definitive prospective trials makes it difficult to draw definitive conclusions as to the benefit of any adjuvant strategy. Nevertheless, several retrospective series and analyses from population-based databases, including the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database, support benefit for adjuvant therapy. Given these findings and the poor prognosis of patients with resected GBC, especially those with ≥T2N0 disease, adjuvant therapy is routinely recommended to patients with resected GBC at many institutions. The following sections will review the available data on adjuvant therapy for a variety of adjuvant therapy strategies.

The benefits of adjuvant therapy following curative-intent surgery for biliary tract cancer (intrahepatic and extrahepatic bile ducts as well as GBC) were addressed in a meta-analysis that included a single randomized trial of chemotherapy alone [29], two SEER registry analyses, and 17 retrospective institutional series, altogether totaling 6712 patients, of whom 1797 received some form of adjuvant therapy [30]. To be eligible, studies had to include patients who had curative-intent surgery alone (defined as negative [R0] or microscopically positive [R1] margins) as a control group. There were eight studies of RT plus chemotherapy, three of chemotherapy alone, and nine of RT alone. Only five of the trials were conducted in GBC (one of which was the randomized trial of chemotherapy discussed above [29]), and four studied external beam RT, two with concomitant chemoradiotherapy.

The following results were noted:

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

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

●Patients with node-positive and margin-positive disease derived the clearest survival benefit from adjuvant therapy:

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

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

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

●There were only limited data to address the benefit of chemotherapy in patients with node-negative disease. In an exploratory analysis, the benefit of adjuvant chemotherapy was of a greater magnitude in studies in which at least 50 percent of the patients had node-positive disease, R1 disease, or both than it was in studies that did not include many patients with node-positive or R1 disease.

While this analysis supports the benefit of adjuvant therapy for high-risk subgroups with GBC, it is based predominantly on retrospective data. Further, it does not resolve the question as to the best treatment strategy (ie, chemoradiotherapy versus chemotherapy alone) for high-risk patients or adequately address the benefit of adjuvant therapy for patients with low-risk (ie, node-negative) disease. Randomized trials remain needed in this area. (See 'Chemotherapy alone versus chemoradiotherapy' below.)

Benefit of individual strategies

Chemotherapy alone — The pattern of disease recurrence in completely resected GBC, in which the majority of patients have distant failure as a component of initial disease recurrence, suggests that chemotherapy might be a more rational adjuvant treatment strategy than RT with or without concurrent chemotherapy. (See 'Patterns of disease recurrence' above.)

However, the available data are inconclusive as to the benefit of chemotherapy in patients with resected GBC. Although most (but not all [31]) retrospective single-institution series and population-based database analyses have suggested some degree of benefit from adjuvant chemotherapy [32-37] results from prospective randomized trials have been discordant, and the small number of patients with GBC enrolled in each of these trials compromises interpretation of most of the studies:

●Positive trials

•BILCAP trial – In the largest adjuvant chemotherapy trial, the phase III BILCAP trial, 447 patients with completely resected cholangiocarcinoma or muscle-invasive (ie, T1b or higher) GBC (n = 79, 18 percent) were randomly assigned to eight cycles of capecitabine (1250 mg/m² twice daily on days 1 to 14 every 21 days) or placebo [38]. Overall, 207 (46 percent) had node-negative disease; the margins were negative (R0 resection) in 279 (62 percent) and microscopically positive (R1 resection) in 168 (38 percent). In the entire cohort, there was a potentially clinically meaningful, although not statistically significant, improvement in overall survival with capecitabine according to the intent-to-treat analysis (median 51 versus 36 months, hazard ratio [HR] 0.81, 95% CI 0.63-1.04). The benefit was statistically significant when ineligible patients (four in each group) and the 10 patients who received no postoperative capecitabine doses despite being randomized to receive the drug were eliminated from the analysis (per protocol analysis, median overall survival 53 versus 36 months, HR 0.75, 95% CI 0.58-0.97). The analysis was not stratified according to primary tumor site, and only a small minority of patients in this study had GBC (18 percent).

The survival curves did not separate over time, and comparable results were reported in a later analysis with median follow-up 106 months [39].

Largely based on the initial results, a year 2019 Clinical Practice Guideline from the ASCO suggests that patients with resected biliary tract cancer should be offered six months of adjuvant capecitabine alone, and that chemoradiotherapy should be offered only to patients with resected GBC who have an R1 surgical margin. We agree with this recommendation.

•Japanese trial – Benefit for adjuvant chemotherapy was also suggested in a single multicenter trial of 140 patients from Japan that compared surgery with and without postoperative chemotherapy (two courses of mitomycin plus infusional fluorouracil [FU], followed by prolonged oral administration of FU until tumor progression) in patients with biliary tract cancer [29]. Ninety percent of enrolled patients had node-positive disease. Among the 112 patients with GBC, the five-year survival rate was significantly higher in patients who received chemotherapy (26 versus 14 percent). However, the intent-to-treat analysis failed to demonstrate a statistically significant benefit for chemotherapy (median survival 16.4 versus 14.1 months). Furthermore, when stratified according to the type of surgery, the benefit of chemotherapy was statistically significant only for those undergoing a noncurative resection (9 versus 0 percent, p = 0.02) but not a curative resection (46 versus 31 percent, p = 0.15).

●Negative trials – Two other trials have failed to document a benefit from adjuvant chemotherapy after potentially curative resection of GBC:

•PRODIGE 12 trial – Benefit for six months of gemcitabine plus oxaliplatin adjuvant chemotherapy versus observation could not be shown in the randomized PRODIGE 12-ACCORD 18-UNICANCER GI trial of 196 patients with resected biliary tract cancer (19 percent GBC) [40]. The majority (86 percent) had R0 resections, and approximately 50 percent had node-positive disease. At a median follow-up of 47 months, adjuvant chemotherapy did not significantly improve relapse-free or overall survival (three-year survival 60 versus 65 percent in the chemotherapy and surveillance groups, respectively). Preplanned subgroup analysis failed to demonstrate any subgroup with a benefit from adjuvant chemotherapy, including those with GBC.

•Indian trial – A small randomized Indian trial conducted exclusively in 100 patients with resected GBC also failed to demonstrate a significant survival benefit from six postoperative courses of gemcitabine plus cisplatin compared with observation alone [41].

●Retrospective analyses – Information on the benefit of adjuvant chemotherapy is also available from retrospective analyses of several large databases:

•As will be discussed below, data from a modeling analysis that used the linked SEER-Medicare database on 1137 patients with resected GBC concluded that patients with ≥T2 or node-positive disease derived the greatest benefit from adjuvant chemoradiotherapy, and that in virtually all cases, chemoradiotherapy outperformed chemotherapy alone [42]. (See 'Prediction models' below.)

•Conflicting results are available from two different analyses based on data from the NCDB:

In an analysis of data on 5029 patients diagnosed with T1-3N0-1 GBC, treated with surgical resection, and reported to the NCDB between 2005 and 2013, all adjuvant therapies were associated with a significant improvement in three-year survival relative to surgery alone (chemoradiotherapy adjusted HR 0.47 [95% CI 0.39-0.58], chemotherapy alone adjusted HR 0.77 [95% CI 0.61-0.97], RT alone adjusted HR 0.63 [95% CI 0.44-0.92]) [37].

By contrast, a separate analysis of 4775 patients diagnosed with T2-3 or node-positive GBC, resected with grossly negative margins, and reported to the NCDB between 2004 and 2011 failed to find a survival advantage from any form of adjuvant therapy [43]. Overall survival at three years was 40 percent and was unaffected by adjuvant therapy after adjusting for multiple confounders (HR 1.01, 95% CI 0.92-1.10). The authors themselves stated that surgical techniques and adjuvant therapy strategies were not optimized.

•Some investigators have attempted to stratify the benefit of chemotherapy according to histologic prognostic factors. As an example, in a study of 266 patients undergoing curative intent surgery for incidental GBC, 99 of whom received adjuvant chemotherapy, five factors (margin status, histologic grade of differentiation, tumor (T) stage, nodal metastases, and residual disease) were used to construct a model to predict survival [12]. The likelihood of survival at five years was incrementally decreased among patients in the low-, intermediate- and high-risk groups (69, 56, and 30 percent, respectively), while the benefit of adjuvant chemotherapy appeared limited to those with intermediate- or high-risk tumors. Interpretation of these data is limited by the low utilization of chemotherapy in this cohort, selection bias, marked variability in the types of resection used, and in the adjuvant therapy regimens used.

It is difficult to use any of these analyses to come to any firm conclusions given their retrospective nature and the high likelihood that selection bias could have influenced the results.

Is there an optimal regimen? — If adjuvant chemotherapy is chosen, we suggest single-agent capecitabine for most patients, largely based on the results of the BILCAP trial. However, we acknowledge the limitations of this trial and the lack of comparator trials of alternative chemotherapy regimens. (See 'Chemotherapy alone' above.)

Fluoropyrimidines have been used for the treatment of advanced biliary tract cancer. However, the failure of adjuvant leucovorin-modulated FU to significantly improve survival after resection of periampullary cancer in the ESPAC-3 trial [44] has tempered enthusiasm for use of this agent in the adjuvant treatment of other biliary tract cancers, including GBC. (See "Ampullary carcinoma: Treatment and prognosis", section on 'Chemotherapy alone'.)

Newer orally active fluoropyrimidines include capecitabine, an oral prodrug of FU, and S-1, an oral fluoropyrimidine that includes three different agents: Ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of DPD [dihydropyrimidine dehydrogenase]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea).

●The BILCAP United Kingdom randomized trial of capecitabine versus placebo after resection of biliary tract cancer (described above) supports the potential benefit of single-agent capecitabine, although the data are less than definitive.

●A Japanese trial demonstrated the feasibility of adjuvant S-1 after resection of biliary tract cancer; a multicenter randomized trial of S-1 versus observation has been completed but not yet reported [45].

Given the efficacy of gemcitabine in the advanced disease setting, this agent has been used by many in the adjuvant setting [36,46]. There are no randomized trials comparing gemcitabine alone with observation in patients with resected GBC. In the setting of resected periampullary cancer, the ESPAC-3 trial demonstrated a nonsignificant difference in median survival between gemcitabine-treated and observed patients (median 46 versus 35 months, HR 0.77, 95% CI 0.57-1.05), although in a secondary analysis adjusting for predefined prognostic variables, there was a statistically significant survival benefit for gemcitabine alone (HR 0.70, 95% CI 0.51-0.97) [44]. These data are described in detail elsewhere. (See "Ampullary carcinoma: Treatment and prognosis", section on 'Chemotherapy alone'.)

The utility of gemcitabine-based combination regimens is uncertain:

●In a retrospective review of 103 patients with resected biliary tract cancer, of whom 50 had received postoperative treatment with S-1 plus gemcitabine while 53 had not, five-year survival rates were higher in those who received combination chemotherapy (57 versus 24 percent) [35]. However, retrospective series such as this are limited by selection bias in that fitter patients may have been offered adjuvant therapy while less fit patients were not. S-1 is not available in the United States. This combination warrants further evaluation in a randomized trial with survival as the primary endpoint.

●Given the data in advanced disease that demonstrate superiority of gemcitabine plus cisplatin over gemcitabine alone [47], some consider this regimen to represent a reasonable alternative to a fluoropyrimidine or gemcitabine alone for patients who can tolerate cisplatin. However, there are no data supporting benefit for this or any other gemcitabine combination regimen in the adjuvant setting at present. (See "Treatment of advanced, unresectable gallbladder cancer", section on 'Gemcitabine plus cisplatin'.)

Several trials are ongoing to address the superiority of gemcitabine combinations in the adjuvant setting, and eligible patients should be encouraged to enroll:

•A German phase III trial of gemcitabine plus cisplatin versus observation following resection of biliary tract cancer is currently underway.

•Similarly, a French trial examining the benefit of gemcitabine plus oxaliplatin versus observation after resection of biliary tract cancer is now complete.

Consensus-based guidelines from the NCCN [48] recommend single-agent gemcitabine or a fluoropyrimidine in this setting. We agree with this recommendation.

Chemoradiotherapy — Among patients undergoing potentially curative resection, postoperative external beam RT can diminish local recurrence rates, but the lack of randomized trials makes it difficult to ascertain whether survival is favorably impacted. Nevertheless, impressions of a survival advantage have been reported in many (but not all [7,32,49,50]) retrospective reports in which either RT alone, chemotherapy alone, or chemoradiotherapy (generally with a concomitant fluoropyrimidine) was administered [51-61]. In most cases, the authors concluded that the patients who underwent RT as a component of therapy (particularly at doses ≥40 Gy) [53,62] survived longer than those who did not.

Benefit has varied according to tumor stage and extent of surgery. As examples:

●A retrospective analysis of a multi-institutional database of 291 patients with GBC who underwent curative-intent resection between 2000 and 2015 included 186 who underwent surgery alone, 61 who received adjuvant chemotherapy, and 44 who received adjuvant chemoradiotherapy [60]. In multivariate analysis, after controlling for T stage, tumor size, the rate of nodal positivity, lymphovascular invasion, positive resection margins, and postoperative complications, receipt of adjuvant therapy was associated with a significant survival benefit compared with surgery alone (HR for chemotherapy 0.38, 95% CI 0.23-0.65; HR for chemoradiotherapy 0.26, 95% CI 0.15-0.43). The survival benefit of adjuvant therapy was limited to those patients with high-risk features (American Joint Committee on Cancer [AJCC]/Union for International Cancer Control [UICC] T3 or 4 stage (table 1), lymph node metastases, and R1 resection).

●In a retrospective study of 73 patients from the Mayo Clinic, no significant difference was seen in survival when patients receiving FU and RT were compared with those treated with surgery alone. However, when analyzed by stage, those patients with a higher stage and involved lymph nodes appeared to derive a significant benefit [53]. This finding was also noted in a year 2012 meta-analysis of adjuvant strategies (predominantly RT and chemoradiotherapy) following resection of GBC. (See 'Chemotherapy alone versus chemoradiotherapy' below.)

●A feasibility study conducted by SWOG supports the use of capecitabine-based chemoradiotherapy in conjunction with capecitabine plus gemcitabine [28]. In this nonrandomized study, 79 patients with resected extrahepatic biliary cancer or GBC received four cycles of gemcitabine (1000 mg/m² intravenously on days 1 and 8) plus capecitabine (1500 mg/m² per day on days 1 to 14) followed by concomitant capecitabine (1330 mg/m² per day) and RT (45 Gy to regional lymphatics, 54 to 59.4 Gy to tumor bed). The two-year survival rate was 65 percent. The most common grade 3 to 4 adverse effects were neutropenia (44 percent), hand-foot syndrome (11 percent), and diarrhea (8 percent).

●Benefit for chemoradiotherapy is further supported by an analysis derived from the NCDB of 5029 patients diagnosed with T1-3N0-1 GBC and treated with surgical resection from 2005 and 2013 [37]. Any adjuvant treatment was associated with improved three-year overall survival (HR for death with chemoradiotherapy was 0.47 [95% CI 0.39-0.58], while for chemotherapy alone, it was 0.77 [95% CI 0.61-0.97], and for RT alone, it was 0.63 [95% CI 0.44-0.92]). When outcomes were analyzed according to T and N categories and margin status, adjuvant chemoradiotherapy was associated with significantly improved survival in all categories except T1N0 and in patients with negative and positive margins.

However, it is entirely possible that the apparent survival prolongation in all of these studies is attributable to selection of fitter and younger patients for adjuvant therapy and/or tumor biology, and thus, is unrelated to the use of RT or chemoradiotherapy. On the other hand, in the NCDB series reported above, advanced tumor stage, large primary tumor size, and involvement of lymph nodes (which would all predict for a worse outcome) were associated with a higher likelihood of receiving some form of adjuvant therapy [37].

Adjuvant intraoperative radiation therapy — The limited radiation tolerance of normal tissues surrounding the gallbladder led to the introduction of intraoperative radiation therapy (IORT), a technique that enables the delivery of a large dose of RT to the exact tumor area while protecting adjacent radiosensitive structures. Early reports suggest a benefit for IORT for both cure and palliation of GBC [47,63,64]. In one nonrandomized series, 17 of 27 patients undergoing resection for T4 or N1 (as defined by the 2010 Tumor, Node, Metastasis [TNM] staging for GBC, in which N1 disease is defined by the location of the positive nodes (table 3)) GBC received IORT with or without postoperative external beam RT [63]. The three-year cumulative survival following resection plus IORT versus resection alone was 10 versus 0 percent. However, these are all retrospective series, and interpretation is subject to the same selection bias as with postoperative external beam RT. Given the lack of high-quality evidence to support benefit, the lack of widespread availability of IORT, and the logistics of intraoperative treatment, routine use of IORT cannot be considered a standard component of therapy for GBC.

Chemotherapy alone versus chemoradiotherapy — There are no randomized trials directly comparing chemotherapy alone versus concomitant chemoradiotherapy with or without adjuvant chemotherapy. Information on the relative benefits of these approaches is available from a meta-analysis and from prediction models.

Meta-analysis — As noted above, the benefits of adjuvant therapy following curative-intent surgery for biliary tract cancer (intrahepatic and extrahepatic bile ducts as well as GBC) were addressed in a meta-analysis that predominantly evaluated data from retrospective series [30]. To be eligible, studies had to include patients who had curative-intent surgery alone (defined as R0 or R1 margins) as a control group. There were eight studies of RT plus chemotherapy, three of chemotherapy alone, and nine of RT alone. Only five of the trials were conducted in GBC, one of which was the randomized trial of chemotherapy discussed above [29], and four studied external beam RT, two with concomitant chemoradiotherapy. (See 'Benefits' above.)

The following results were noted:

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

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

●There were only limited data to address the benefit of chemotherapy in patients with node-negative disease. In an exploratory analysis, the benefit of adjuvant chemotherapy was of a greater magnitude in studies in which at least 50 percent of the patients had node-positive, R1 disease, or both than it was in studies that did not include many patients with node-positive or R1 disease.

This analysis does not resolve the question as to the best treatment strategy (ie, chemoradiotherapy versus chemotherapy alone) for high-risk patients.

National Cancer Database analysis — Benefit for chemoradiotherapy is further supported by an analysis derived from the NCDB of 5029 patients diagnosed with T1-3N0-1 GBC and treated with surgical resection from 2005 and 2013 [37]. Three-year overall survival was most improved by chemoradiotherapy (HR for death 0.47 [95% CI 0.39-0.58]), while for chemotherapy alone, the HR for death was 0.77 (95% CI 0.61-0.97).

Prediction models — One group of investigators attempted to construct a prediction model for estimating the survival benefit of adjuvant chemoradiotherapy that utilized the linked SEER-Medicare database (which allows claims data on chemotherapy use to be collected) to study 1137 Medicare beneficiaries with resected GBC who were treated between 1995 and 2005 [42]. Forty-one percent had node-positive disease, and 55 percent had T3/4 primary tumors. Overall, 126 patients received adjuvant chemotherapy, and an additional 126 received both chemotherapy and RT within six months of diagnosis and, thus, were considered to have received chemoradiotherapy. Treated patients tended to be younger and have higher T and N stages. However, propensity-score weighting was used to balance all covariates between treated and untreated groups. Multivariate regression survival analysis was performed using several different modeling methods, and the best performing of these was used to construct a nomogram (available online) that calculates the expected survival benefit from adjuvant chemotherapy and chemoradiotherapy. The authors concluded that patients with ≥T2 or node-positive disease derived the greatest benefit from chemoradiotherapy and that, in virtually all cases, chemoradiotherapy outperformed chemotherapy alone.

Guidelines from expert groups — Consensus-based guidelines for adjuvant therapy after resection of bile duct cancer are available from three expert groups; not surprisingly, they differ substantially:

●A year 2019 Clinical Practice Guideline from ASCO suggests that all patients with resected GBC should be offered six months of adjuvant capecitabine, largely based on the BILCAP trial [38]. They suggest offering chemoradiotherapy in addition to chemotherapy only for those who have a microscopically positive surgical margin.

●Guidelines from the NCCN [48] suggest the following:

•For all patients with resected, T1b or higher margin-negative, node-negative tumors and those with carcinoma in situ at the margin, options include observation, fluoropyrimidine-based chemoradiotherapy, or fluoropyrimidine-based or gemcitabine-based chemotherapy. Observation alone is recommended for patients with resected (incidentally detected) T1a disease and negative margins.

•For patients with resected margin-positive or node-positive disease, options include fluoropyrimidine-based or gemcitabine-based chemotherapy, fluoropyrimidine-based chemoradiotherapy, or a combined approach.

●Year 2016 consensus-based guidelines from the European Society of Medical Oncology (ESMO) suggest that adjuvant therapy (RT, chemoradiotherapy, or chemotherapy alone) may be offered to patients with resected GBC on the understanding that the evidence base is weak and only after risk-benefit assessment; participation in clinical trials is encouraged [65].

POST-TREATMENT SURVEILLANCE — There are no evidence-based guidelines for appropriate follow-up after treatment of gallbladder cancer (GBC) and no data to support benefit from aggressive post-treatment surveillance. Consensus-based guidelines from the National Comprehensive Cancer Network [48] suggest that imaging can be "considered" every six months for two years as clinically indicated, then annually up to five years. Testing of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA 19-9) can be "considered" as clinically indicated.

We monitor patients closely with liver function tests and tumor markers (CEA and CA 19-9) every three to four months for the first two years after surgery, followed by every six months for one more year. We do not routinely perform post-treatment surveillance imaging for asymptomatic patients.

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

SUMMARY AND RECOMMENDATIONS

●Gallbladder cancer (GBC) has traditionally been associated with a poor prognosis, attributed typically to the advanced stage at diagnosis, which is due both to the vagueness and nonspecificity of symptoms, and the anatomic position of the gallbladder. In contrast to patients who have margin-positive resections, in whom locoregional recurrences predominate, the pattern of disease recurrence following complete resection of GBC is both distant and local. (See 'Prognosis and patterns of spread' above.)

●The benefit of adjuvant radiation therapy (RT) or concomitant chemoradiotherapy after resection of GBC has not been tested in randomized controlled trials. However, impressions of a survival advantage have been reported in many retrospective reports in which either RT alone or chemoradiotherapy (generally with a concomitant fluoropyrimidine) was administered. (See 'Chemoradiotherapy' above.)

The available data from randomized trials are inconclusive as to the benefit of chemotherapy in patients with resected GBC. However, at least two trials have demonstrated a potentially clinically meaningful, albeit statistically insignificant, survival benefit. (See 'Chemotherapy alone' above.)

In a meta-analysis derived mainly from retrospective reports, patients with node-positive and margin-positive disease seem to derive the clearest survival benefit from any form of adjuvant therapy. (See 'Benefits' above.)

●Despite the paucity of high-quality evidence to support benefit, we suggest adjuvant therapy for all patients with completely resected muscle-invasive (≥T1b), node-positive, or margin-positive GBC (Grade 2C). Although guidelines from the American Society of Clinical Oncology suggest adjuvant therapy for all patients with resected GBC, we would not offer therapy to a patient with a resected T1a, node-negative tumor, given that these patients were not eligible for either the BILCAP or the Southwest Oncology Group (SWOG) trials. This approach is consistent with National Comprehensive Cancer Network guidelines. (See 'Indications' above and 'Guidelines from expert groups' above.)

There is no consensus as to the optimal adjuvant approach. Given the high rate of distant recurrence, especially after a complete resection, and the results of the phase III BILCAP trial, we prefer six months of postoperative chemotherapy alone with capecitabine monotherapy for most patients. If capecitabine is chosen, we would start treatment with no more than a 1500 mg total dose twice daily. (See 'Chemotherapy alone' above.)

An alternative approach combining concomitant fluoropyrimidine-based chemoradiotherapy with four months of systemic chemotherapy is also acceptable, particularly for patients with margin-positive disease. In this situation, the choice of chemotherapy can be either capecitabine monotherapy or capecitabine plus gemcitabine (eg, as was used in SWOG S0809 (table 2)). (See 'Chemoradiotherapy' above and "Treatment protocols for hepatobiliary cancer".)

For patients who receive chemoradiotherapy plus adjuvant chemotherapy, the optimal way to integrate chemoradiotherapy and chemotherapy is uncertain. In general, it is preferable to start with chemotherapy first, to complete three to four months of systemic exposure, based on the rationale that this approach will avoid RT for patients who are destined to develop early distant metastases and may not need it.

●There are no data to support aggressive post-treatment surveillance. We monitor patients closely with liver function tests and tumor markers (carcinoembryonic antigen [CEA] and cancer antigen 19-9 [CA 19-9]) every three to four months for the first two years after surgery, followed by every six months for one more year. We perform reimaging only as clinically indicated. (See 'Post-treatment surveillance' above.)