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Adjuvant treatment for localized, resected gallbladder cancer

Authors: Bhoomi Mehrotra, MD, Tanios Bekaii-Saab, MD

Section Editors: Kenneth K Tanabe, MD, Stanley W Ashley, MD
Deputy Editor: Diane MF Savarese, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2017. | This topic last updated: Jan 04, 2018.

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' and "Surgical management of gallbladder cancer".)

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 'Managing an incidental gallbladder cancer'.)

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 "Treatment of localized
cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis".)

PROGNOSIS AND PATTERNS OF SPREAD — The current (eighth) edition of the American Joint Committee on
Cancer (AJCC)/Union for International Cancer Control (UICC) staging criteria contains several changes compared with
the earlier 2010 edition (table 1) [5]. 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) [6]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section
on 'TNM staging system'.)

The poor prognosis associated with 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 [7]. 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.

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 [8]. 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 [9-11], though locoregional
recurrences also occur [12]:

● 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 [9].

● In another retrospective review of 166 patients undergoing surgical resection with curative intent for GBC, 53 had
a tumor recurrence [13]. 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 — 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 ≥T2 (table 1), node-positive, or margin-positive GBC. There is no consensus as to the optimal adjuvant
approach. Given the high rate of distant recurrence, especially after completely resected GBC, we prefer six months of
postoperative chemotherapy alone. The choice of drug (gemcitabine, fluorouracil [FU], capecitabine) is empiric. An
alternative approach combining concomitant fluoropyrimidine-based chemoradiotherapy with four months of systemic
chemotherapy with capecitabine plus gemcitabine (eg, as was used in Southwest Oncology Group [SWOG] S0809
(table 2) [14]) is also acceptable, particularly for patients with margin-positive disease. (See "Treatment protocols for
hepatobiliary cancer".)

For patients who receive both chemoradiotherapy and adjuvant 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 no adequately powered randomized trials of adjuvant therapy to guide clinicians treating
patients with GBC. The lack of 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 ≥T2 disease,
adjuvant therapy is routinely recommended to patients with ≥T2 (table 1), node-positive, or margin-positive tumors at
many institutions. The following sections will review the available data on adjuvant therapy for a variety of adjuvant
therapy strategies.

Radiation and chemoradiotherapy — The role of adjuvant RT, with or without concomitant chemotherapy, in the
treatment of GBC is not well established. 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 [13,15-17]) retrospective reports in which either RT alone, chemotherapy alone, or chemoradiotherapy
(generally with a concomitant fluoropyrimidine) was administered [18-28]. In most cases, the authors concluded that
the patients who underwent RT as a component of therapy (particularly at doses ≥40 Gy) [20,29] 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 [27]. 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 (hazard ratio [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 macroscopically incomplete [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 [20].
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 [14]. 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 [30]. 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], 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 [30].

Adjuvant IORT — 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 [31-33]. 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 [31]. 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 — 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 [34]) retrospective single-institution series and population-based database analyses have
suggested some degree of benefit from adjuvant chemotherapy [17,30,35-38], few prospective randomized trials have
been conducted, and the small number of patients with GBC enrolled in each of these trials compromises
interpretation of the results:

● A single multicenter trial of 140 patients from Japan comparing surgery with and without postoperative
chemotherapy (two courses of mitomycin C plus infusional FU, followed by prolonged oral administration of FU
until tumor progression) showed a modest benefit from adjuvant chemotherapy [39]. 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).

● In the phase III BILCAP trial, 447 patients with completely resected cholangiocarcinoma or 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 [40]. 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 a preliminary
report presented at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO), 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, HR 0.81, 95% CI 0.63-1.06).
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.

● On the other hand, benefit for chemotherapy could not be shown in the randomized PRODIGE 12-ACCORD 18
(UNICANCER GI) trial, which randomly assigned 196 patients with resected biliary tract cancer (19 percent GBC)
to surveillance only or 12 cycles of gemcitabine (1000 mg/m2 day 1) plus oxaliplatin (85 mg/m2 day 2) given every
21 days [41]. In a preliminary report presented at the 2017 ASCO Gastrointestinal Cancers Symposium, with a
median follow-up of 44 months, adjuvant chemotherapy did not significantly improve relapse-free survival, the
primary endpoint (at four years, 39 versus 33 percent; HR 0.83, 95% CI 0.58-1.19).

● 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 upon data from the NCDB:

In an analysis of data on 5029 patients diagnosed with T1-3 N0-1 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]) [30].

In 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.

• A preliminary report of an analysis of data on 975 cases of GBC derived from the German Registry of
Incidental Gallbladder Carcinoma concluded that there was a highly significant survival benefit for adjuvant
therapy in T2 disease and a trend toward better survival in resected T3 disease [44]. The specific adjuvant
strategies utilized were not stated.

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.

Choice of regimen — If adjuvant chemotherapy is utilized, the optimal regimen is not established.
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
[45] 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):

● A preliminary report of the BILCAP United Kingdom randomized trial of capecitabine versus placebo after
resection of a biliary tract cancer, described above, supports the potential benefit of single-agent capecitabine.
(See 'Chemotherapy alone' above.)

● 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 [46].

Given the efficacy of gemcitabine in the advanced disease setting, this agent has been used by many in the adjuvant
setting [38,47]. 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) [45]. 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) [37]. 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 [33], 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 of 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 National Comprehensive Cancer Network (NCCN) recommend single-agent
gemcitabine or a fluoropyrimidine in this setting. We agree with this recommendation.

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 — 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 the single
randomized trial of chemotherapy alone described above [39], two SEER registry analyses, and 17 retrospective
institutional series, altogether totaling 6712 patients, of whom 1797 received some form of adjuvant therapy [48]. 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 [39], 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] 0.74, 95% CI 0.55-1.01). The results were similar when gallbladder and bile
duct cancers were analyzed independently. However, the survival benefit from adjuvant therapy was statistically
significant when data from the two large registry series (n = 1233 patients) were excluded (OR 0.53, 95% CI 0.39-
0.72).

● The benefits of adjuvant therapy were modality dependent; in a combined analysis of 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 an 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, 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 upon 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.

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 [49]) 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 two expert groups:

● Guidelines from the NCCN suggest that either adjuvant fluoropyrimidine-based chemoradiotherapy, or
chemotherapy alone with a single-agent fluoropyrimidine or gemcitabine be "considered" after resection for all
except T1N0 tumors.

● 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 on the
understanding that the evidence base is weak and only after risk-benefit assessment; participation in clinical trials
should be encouraged [50].

POSTTREATMENT 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 posttreatment surveillance.
Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest that imaging can be
"considered" every six months for two years as clinically indicated. 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 do not routinely perform
posttreatment surveillance imaging for asymptomatic patients.

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

● 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 radiation alone or chemoradiotherapy (generally with a concomitant
fluoropyrimidine) was administered. (See 'Radiation and 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.)

● Despite the paucity of high-quality evidence to support benefit, we suggest adjuvant therapy for patients with
completely resected ≥T2 (table 1), node-positive, or margin-positive GBC (Grade 2C). There is no consensus as
to the optimal adjuvant approach. Given the high rate of distant recurrence, especially after completely resected
GBC, we prefer six months of postoperative chemotherapy alone. The choice of drug (gemcitabine, fluorouracil,
capecitabine) is empiric. An alternative approach combining concomitant fluoropyrimidine-based
chemoradiotherapy with four months of systemic chemotherapy with capecitabine plus gemcitabine (eg, as was
used in Southwest Oncology Group [SWOG] S0809 (table 2) [14]) is also acceptable, particularly for patients with
margin-positive disease. (See "Treatment protocols for hepatobiliary cancer".)

These recommendations are consistent with consensus-based guidelines from the National Comprehensive
Cancer Network (NCCN), which suggest consideration of fluoropyrimidine-based chemoradiotherapy or
chemotherapy alone using a gemcitabine- or fluoropyrimidine-containing regimen after resection for all except
T1N0 (table 1) GBC. (See 'Guidelines from expert groups' above.)

For patients who receive chemoradiotherapy and 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 posttreatment 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 'Posttreatment surveillance' above.)

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and follow-up. Ann Oncol 2016; 27:v28.

Topic 2525 Version 31.0

GRAPHICS

Gallbladder cancer TNM staging AJCC UICC 2017

Primary tumor (T)

T category T criteria

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 Tumor invades the lamina propria or muscular layer

T1a Tumor invades the lamina propria

T1b Tumor invades the muscular layer

T2 Tumor invades the perimuscular connective tissue on the peritoneal side, without
involvement of the serosa (visceral peritoneum).
Or tumor invades the perimuscular connective tissue on the hepatic side, with no
extension into the liver.

T2a Tumor invades the perimuscular connective tissue on the peritoneal side, without
involvement of the serosa (visceral peritoneum)

T2b Tumor invades the perimuscular connective tissue on the hepatic side, with no extension
into the liver

T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or
one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas,
omentum, or extrahepatic bile ducts

T4 Tumor invades the main portal vein or hepatic artery or invades two or more extrahepatic
organs or structures

Regional lymph nodes (N)

N category N criteria

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastases to one or three regional lymph nodes

N2 Metastases to four or more regional lymph nodes

Distant metastasis (M)

M category M criteria

M0 No distant metastasis

M1 Distant metastasis

Prognostic stage groups

When T is... And N is... And M is... Then the stage group is...
Tis N0 M0 0

T1 N0 M0 I

T2a N0 M0 IIA

T2b N0 M0 IIB

T3 N0 M0 IIIA

T1-3 N1 M0 IIIB

T4 N0-1 M0 IVA

Any T N2 M0 IVB

Any T Any N M1 IVB

TNM: tumor, node, metastasis; AJCC: American Joint Committee on Cancer; UICC: Union for International Cancer Control.

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the
AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.

Graphic 110890 Version 2.0

Survival after resection of gallbladder cancer, stratified by stage according to the 2017 TNM
staging criteria

Comparison of survival according to conventional TNM classification with subclassification of T2 tumors by tumor
location. N factor and M factor were clinically determined on the basis of either histopathologic findings or radiographic
evaluation.

TNM: tumor, node, metastasis.

From: Shindoh J, de Aretxabala X, Aloia TA, et al. Tumor location is a strong predictor of tumor progression and survival in T2
gallbladder cancer: an international multicenter study. Ann Surg 2015; 261:733. DOI: 10.1097/SLA.0000000000000728.
Copyright © 2015 American Surgical Association and European Surgical Association. Reproduced with permission from Lippincott
Williams & Wilkins. Unauthorized reproduction of this material is prohibited.

Graphic 110891 Version 1.0

Adjuvant gemcitabine and capecitabine (GemCap) followed by concurrent capecitabine
and radiotherapy for extrahepatic cholangiocarcinoma and gallbladder carcinoma [1]

Cycle length: 21 days × 4 cycles

Drug Dose and route Administration Given on days

Gemcitabine* 1000 mg/m 2 IV Dilute in 250 mL normal saline (concentration Days 1 and 8
no greater than 40 mg/mL) and administer
over 30 minutes.

Capecitabine ¶ 750 mg/m 2 per dose Twice daily (total dose 1500 mg/m 2 per day). Days 1 through 14
by mouth Swallow whole with water within 30 minutes
after a meal, with each dose as close to 12
hours apart as possible. Do not cut or crush
tablets. Δ

Cycle length: Five to six weeks (chemoradiotherapy ◊)

Capecitabine ¶ 665 mg/m 2 per dose Twice daily (total dose 1330 mg/m 2 per day). Concurrently (seven
by mouth Swallow whole with water within 30 minutes days per week) with
after a meal, with each dose as close to 12 radiation beginning
hours apart as possible. Do not cut or crush day 1
tablets. Δ

Radiotherapy 45 Gy to regional Three dimensional: 30 fractions (54 Gy) or 33 Five days per week
lymph nodes § and 54 fractions for R1 resection (59.4 Gy). beginning week 1 and
to 59.4 Gy to IMRT: 25 fractions (52.5 Gy [or 55 Gy for R1 continuing through
preoperative tumor resection]). week 6
bed

Pretreatment considerations:

Emesis risk LOW for both chemotherapy and chemoradiotherapy.

Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and
vomiting in adults".

Infection Primary prophylaxis with G-CSF is not indicated. [1]

prophylaxis Refer to UpToDate topic on "Prophylaxis of infection during chemotherapy-induced
neutropenia in high-risk adults".

Dose adjustment A lower starting dose of gemcitabine may be needed for patients with liver impairment. [2] A
for baseline liver lower starting dose of capecitabine may be needed for patients with moderate renal
or renal impairment. [3]
dysfunction Refer to UpToDate topics on "Chemotherapy hepatotoxicity and dose modification in patients
with liver disease" and "Chemotherapy-related nephrotoxicity and dose modification in
patients with renal insufficiency".

Monitoring parameters:
CBC with differential and platelet count weekly during treatment.

Assess basic metabolic panel (including serum creatinine) and liver function tests every three weeks prior to each
new chemotherapy cycle and weekly during chemoradiotherapy or otherwise as indicated during treatment.

Monitor for diarrhea, stomatitis, and cutaneous toxicity (palmar-plantar erythrodysesthesias) during treatment.

More frequent anticoagulant response (INR or prothrombin time) monitoring is necessary for patients receiving
concomitant capecitabine and oral coumarin-derivative anticoagulant therapy.

Cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac
arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions
may be more common in patients with a prior history of coronary artery disease.
Refer to UpToDate topic on "Cardiotoxicity of nonanthracycline cancer chemotherapy agents".

Suggested dose modifications for toxicity:

Myelotoxicity This regimen should not be initiated unless neutrophils are ≥1500/microL and platelets are
≥100,000/microL. [1]
Reduce the day 8 gemcitabine dose by 25% for an absolute neutrophil count of 500 to

[4,5]
 1000/microL or a platelet count of 50,000 to 100,000/microL. [4,5]
Decrease gemcitabine by 25% for subsequent cycles for febrile neutropenia, grade 4
hematologic toxicity lasting for more than seven days, or bleeding-associated
thrombocytopenia. [5]

Pulmonary A variety of manifestations of pulmonary toxicity have been reported in patients treated with
toxicity gemcitabine. Discontinue gemcitabine immediately and permanently.
Refer to UpToDate topic on "Pulmonary toxicity associated with antineoplastic therapy:
Cytotoxic agents".

Thrombotic Thrombotic microangiopathy (TMA, also sometimes called thrombotic thrombocytopenic

microangiopathy purpura [TTP] or hemolytic uremic syndrome [HUS]) has been associated with gemcitabine in
individuals who have received a large or small cumulative dose. Consider the possibility of
TMA if the patient develops Coombs-negative hemolysis, thrombocytopenia, renal failure,
and/or neurologic findings. Management consists of drug discontinuation and supportive
care, without plasma exchange, as long as there is high confidence in a drug-induced
etiology rather than TTP.
Refer to UpToDate topic on "Drug-induced thrombotic microangiopathy".

Other toxicity Hold gemcitabine for ≥grade 3 nonhematologic toxicity that is likely related to gemcitabine
(including until it decreases ≤grade 1. [5] Restart gemcitabine with a 25% dose reduction.
hepatotoxicity) Gemcitabine is commonly associated with a transient rise in serum transaminases, but these
are seldom of clinical significance. There is insufficient information from clinical studies to
allow clear dose recommendations in these patients.
Refer to UpToDate topic on "Chemotherapy hepatotoxicity and dose modification in patients
with liver disease".
For capecitabine:
Grade 2: For the first, second, and third occurrence, hold capecitabine therapy. After
resolution to grade 1 or less, resume treatment (first occurrence, no dosage adjustment;
second occurrence, 75% of the starting dose; third occurrence, 50% of the starting
dose). [3] For the fourth occurrence of a grade 2 toxicity, discontinue capecitabine
therapy.
Grade 3: For the first and second occurrence, hold capecitabine therapy. After resolution
to grade 1 or less, resume treatment at a reduced dose (first occurrence, 75% of the
starting dose; second occurrence, 50% of the starting dose). For the third occurrence of a
grade 3 toxicity, discontinue capecitabine therapy.
Grade 4: Discontinue capecitabine therapy. Alternatively, hold capecitabine therapy, and
begin next treatment at 50% of the starting dose when toxicity resolves to grade 1 or
less; discontinue treatment for first recurrence of grade 4 toxicity.
NOTE: Severe diarrhea, mucositis, and myelosuppression after capecitabine should prompt
evaluation for dihydropyrimidine dehydrogenase deficiency. Refer to UpToDate topic on
"Enterotoxicity of chemotherapeutic agents".

Omitted capecitabine doses for toxicity are not replaced or restored. Resume treatment with the planned
next cycle.

If there is a change in body weight of at least 10%, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be other acceptable
methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who
should use independent medical judgment in the context of individual circumstances to make
adjustments, as necessary.

IV: intravenous; Gy: gray; IMRT: intensity-modulated radiotherapy; G-CSF: granulocyte colony stimulating factor; CBC:
complete blood count; INR: international normalized ratio; ULN: upper limit normal.
* Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).
¶ No capecitabine dose has been shown to be safe in patients with complete dihydropyrimidine dehydrogenase (DPD)
deficiency, and data are insufficient to recommend a dose in patients with partial DPD activity.
Δ Extemporaneous compounding of liquid dosage forms has been recommended, but IV therapies may be more appropriate for
patients with significant swallowing difficulty.
◊ Proceed with chemoradiotherapy if no progression on reimaging after four cycles of chemotherapy with gemcitabine and
capecitabine.
§ Regional lymph nodes include: Retropancreaticoduodenal, celiac, and portal vein nodes.

References: ​
1. Ben-Josef E, et al. J Clin Oncol 2015; 33:2617.
2. Gemcitabine injection. United States Prescribing Information. US National Library of Medicine. (Available online at
 dailymed.nlm.nih.gov, accessed on August 30, 2016).
3. Capecitabine. United States Prescribing Information. US National Library of Medicine. (Available online at
www.dailymed.nlm.nih.gov, accessed on August 30, 2016).
4. Riechelmann RP, et al. Cancer 2007; 110:1307.
5. Knox JJ, et al. J Clin Oncol 2005; 23:2332.

Graphic 107377 Version 9.0

TNM staging of gallbladder cancer

Primary tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 Tumor invades lamina propria or muscular layer

T1a Tumor invades lamina propria
T1b Tumor invades muscular layer

T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver

T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent
organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts

T4 Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures

Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein

N2 Metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes

Distant metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

Anatomic stage/prognostic groups

Stage Tis N0 M0
0

Stage T1 N0 M0
I

Stage T2 N0 M0
II

Stage T3 N0 M0
IIIA

Stage T1-3 N1 M0
IIIB

Stage T4 N0-1 M0
IVA

Stage Any T N2 M0
IVB
Any T Any N M1

Note: cTNM is the clinical classification, pTNM is the pathologic classification.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this
material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.

Graphic 70554 Version 12.0

Contributor Disclosures
Bhoomi Mehrotra, MD Nothing to disclose Tanios Bekaii-Saab, MD Nothing to disclose Kenneth K Tanabe,
MD Grant/Research/Clinical Trial Support: Nimbus Therapeutics [Hepatocellular carcinoma (ND654, Acetyl Co-A
Carboxylase allosteric inhibitor)]. Consultant/Advisory Boards: Best Doctors [GI cancers; melanoma (Medical care)];
CRICO [Medical malpractice (Case review)]. Patent Holder: EGF SNP to determine risk for HCC [Cirrhosis,
hepatocellular carcinoma]; Use of EGFR inhibitors to prevent HCC [Cirrhosis, hepatocellular carcinoma]. Equity
Ownership/Stock Options: Helix12 [Breast cancer (Company owns IP on selective estrogen receptor modulators for
breast cancer)]. Stanley W Ashley, MD Nothing to disclose Diane MF Savarese, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support
the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

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