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## Complete Summary

#### GUIDELINE TITLE

The role of gemcitabine in the treatment of cholangiocarcinoma and
gallbladder cancer.

#### BIBLIOGRAPHIC SOURCE(S)

Dingle B, Rumble RB, Brouwers M, Gastrointestinal Cancer Disease Site
Group. The role of gemcitabine in the treatment of cholangiocarcinoma
and gallbladder cancer. Toronto (ON): Cancer Care Ontario (CCO); 2005
Apr 26. 16 p. (DQTC-SOS advice report; no. 1). \[18 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebcdqtc1f.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Advanced or metastatic cancer of the gallbladder

-   Cholangiocarcinoma

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Technology Assessment

#### CLINICAL SPECIALTY

Oncology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To evaluate the role of gemcitabine in the treatment of
cholangiocarcinoma and gallbladder cancer

#### TARGET POPULATION

Adult patients with advanced or metastatic cancer of the gallbladder, or
with cholangiocarcinoma, for whom therapy with gemcitabine is being
considered

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Monotherapy with gemcitabine

2.  Combination therapy with gemcitabine with a fluoropyrimidine, such
    as 5-fluorouracil or capecitabine

3.  Surgical resection

#### MAJOR OUTCOMES CONSIDERED

-   Overall response rates

-   Overall survival

-   Adverse effects

-   Quality of life

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Literature Search Strategy**

The MEDLINE database was searched from 1996 to March (week 2) 2005. The
following Medical subject headings (MeSH) \"gemcitabine\" and
\"gallbladder neoplasms\" were combined, and results were limited to
English only. In addition, conference proceedings from the 1998-2004
meetings of the American Society of Clinical Oncology were searched for
abstracts of relevant trials, including the 2004 Gastrointestinal
Cancers Symposium abstracts. The Canadian Medical Association Infobase
(<http://mdm.ca/cpgsnew/cpgs/index.asp>) and the National Guidelines
Clearinghouse (<http://www.guideline.gov/>) were also searched for
existing evidence-based practice guidelines. An additional article not
found in the literature search, as it was too recent to be indexed, was
obtained from a Gastrointestinal Cancer Disease Site Group (DSG) member.

Relevant articles and abstracts were selected and reviewed by two
reviewers, and the reference lists from those sources were searched for
additional trials.

**Inclusion Criteria**

Articles were selected for inclusion in the systematic review of the
evidence if they were fully published English-language reports or
published abstracts of:

1.  Randomized controlled trials (RCTs) comparing gemcitabine, either
    alone or in combination, with best supportive care or other therapy
    in the treatment of cholangiocarcinoma or gallbladder cancer.

2.  Phase II trials reporting on the efficacy or adverse effects
    detected in treatment with gemcitabine, alone or in combination, in
    the treatment of cholangiocarcinoma or gallbladder cancer.

**Exclusion Criteria**

1.  Letters and editorials were not eligible.

#### NUMBER OF SOURCE DOCUMENTS

Thirteen single-arm phase II studies were obtained.

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Expert Consensus (Committee)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

As none of the trials obtained were randomized controlled trials (RCTs),
no pooling of outcome data was possible.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

This advice report, produced by the Program in Evidence-Based Care\'s
(PEBC\'s) Gastrointestinal Cancer Disease Site Group (DSG), is a
convenient and up-to-date source of the best available evidence on the
role of gemcitabine in the treatment of gallbladder cancer developed
through systematic reviews of the available evidence.

The most effective treatment for cancer of the gallbladder is surgical
resection of the primary tumour along with any local spread, but surgery
is dependent upon the patient presenting at an earlier, resectable
stage. Curative resection of cholangiocarcinoma is more complex and is
dependent on the site and extent of the tumour. Five-year survival after
the surgical resection of stage I gallbladder cancer should be greater
than 85%, but drops to 25%, 10%, and 2% for stage II, III, and IV
tumours. For patients with resectable cholangiocarcinoma, five-year
survival rates range from 35% to 45%. There is no generally accepted
standard chemotherapy for advanced, non-resectable, cancer of the
gallbladder or biliary tree. In advanced disease, median survival with
best supportive care is approximately six months, and five-year survival
rates approach 0%. In past phase II studies, response rates for the use
of fluoropyrimidines in this population ranged from 10% to 28%.

Gemcitabine either alone or in combination with other commonly used
drugs such as fluoropyrimidines or cisplatin has shown positive activity
and response in phase II trials for the treatment of advanced biliary
cancer. Single studies of gemcitabine in combination with oxaliplatin
and carboplatin also suggest a similar response.

Considering the low incidence rate of these types of tumours and the
poor performance status of many patients presenting with biliary cancer,
conducting large trials to establish a standard of care is unlikely.
Indeed, a search of the National Cancer Institute\'s Internet clinical
trials database (<http://www.cancer.gov/search/clinical_trials/>) on
March 23, 2005 for reports of new or ongoing trials revealed only two
small Phase II trials (Appendix 3 in the original guideline document).
Information on a third phase II trial (SAKK-44/02) was submitted by an
Ontario clinician. Therefore, treatment decisions must be based on the
balance of predictable toxicities and benefits. While none of the
studies included in this systematic review measured and evaluated
quality-of-life scores, the assumption that some benefit may accrue from
complete and partial responses, if not also from stabilization of the
disease, seems reasonable. Certainly the extension of median survival to
over one year in some studies compares favourably with best supportive
care by as much as six months.

Therefore, administering a trial of gemcitabine in selected patients,
either as a single agent, or in combination with other drugs that have
demonstrated a response in this treatment population, seems reasonable.
In general, fluoropyrimidines have a more favourable toxicity profile
compared with the alkylating platinum compounds (cisplatin, oxaliplatin,
and carboplatin). Considering the improved response rates and survival
in combination therapy, the use of gemcitabine and a fluoropyrimidine
appears to be favoured. A recent article stated that a previous
retrospective review of gemcitabine and continuous infusion
5-fluorouracil (5-FU) showed a similar benefit in terms of response but
with increased line-related infections and thromboembolitic
complications, which suggests that when gemcitabine is given with a
fluoropyrimidine, the fluoropyrimidine of choice should be capecitabine.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

See Appendix 1 in the original guideline document for recommended
regimens and dosages.

-   In appropriate patients with gallbladder cancer or
    cholangiocarcinoma, surgical resection offers the best chance for
    survival and should be the first treatment of choice.

-   For patients who are not considered candidates for surgery with
    curative intent, but who are willing and able to tolerate treatment
    with chemotherapy, considering the lack of an effective standard
    treatment option, gemcitabine, either alone or in combination with a
    fluoropyrimidine such as 5-fluorouracil (5-FU) or capecitabine, is a
    reasonable alternative to best supportive care, although this
    conclusion has not been confirmed with a randomized controlled
    trial.

-   Patients should be encouraged to enroll in randomized controlled
    trials comparing promising new treatments, such as gemcitabine in
    combination with a fluoropyrimidine against other treatments with
    proven response.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The recommendations are supported by single-arm phase II studies.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Five-year survival rates after surgical resection of stage I
    gallbladder cancer may be greater than 85%, but drops to 25%, 10%,
    and 2% for stage II, III, and IV tumours. For patients with
    non-resectable disease who are offered palliative chemotherapy only,
    the five-year survival rate approaches 0%.

-   Gemcitabine either alone, or in combination with fluoropyrimidines,
    cisplatin, oxaliplatin, or carboplatin has shown positive activity
    and response in phase II trials treating advanced biliary cancer.
    Given the more favourable toxicity profile of fluoropyrimidines
    (either 5-fluorouracil/leucovorin or capecitabine) compared with the
    alkylating platinum compounds cisplatin, oxaliplatin, or
    carboplatin, and the apparent improved response rates and survival
    in combination therapy, the use of gemcitabine and a
    fluoropyrimidine is favoured.

-   The expert opinion of the Gastrointestinal Cancer Disease Site Group
    is that some benefit may accrue from complete and partial responses,
    if not also from stabilization of the disease. In some of the phase
    II trials reviewed, the extension of median survival to over one
    year exceeds current results with best supportive care by as much as
    six months.

#### POTENTIAL HARMS

-   Adverse effects observed in the trials of gemcitabine monotherapy
    are described as follows: one trial reported no grade 3-4 adverse
    effects, and one trial reported no grade 4 adverse effects. Two
    trials reported either grade 3 or grade 4 neutropenia. At least one
    trial reported the following grade 3-4 effects: anemia, nausea,
    flu-like symptoms, hemolytic uremic syndrome, and anorexia.
    Generally, the gemcitabine monotherapy trials reported that any
    adverse effects observed were mild and manageable. See Appendix 2 in
    the original guideline document for details of the observed adverse
    effects by trial.

-   A variety of grade 3-4 adverse effects were observed in the trials
    of gemcitabine in combination with other drugs. The three trials
    investigating gemcitabine in combination with cisplatin reported
    granulocytopenia, thrombocytopenia, fever, asthenia, anorexia,
    neutropenia, anemia, and leukopenia. The trial investigating
    gemcitabine in combination with docetaxel reported alopecia,
    nausea/vomiting, mucositis, leukopenia, thrombocytopenia, and
    anemia. The trial investigating gemcitabine in combination with
    5-fluorouracil/leucovorin (5-FU/LV) reported dyspnea,
    nausea/vomiting, fatigue, thrombocytopenia, diarrhea, infection,
    leukopenia, anemia, and elevation of liver enzymes. The trial
    investigating gemcitabine in combination with oxaliplatin reported
    neutropenia, thrombocytopenia, nausea/vomiting, and peripheral
    neuropathy. The trial investigating gemcitabine in combination with
    mitomycin-C reported leukopenia and thrombocytopenia. The trial
    investigating gemcitabine in combination with carboplatin reported
    nausea/vomiting, elevation of liver enzymes, proteinuria, hematuria,
    edema, and fatigue. The trial investigating gemcitabine in
    combination with capecitabine reported neutropenia (one case of
    febrile neutropenia), thrombocytopenia, hand-foot rash, infection,
    fatigue, and thromboembolitis. See Appendix 2 in the original
    guideline document for details of the observed adverse effects by
    trial.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

Care has been taken in the preparation of the information contained in
this document. Nonetheless, any person seeking to apply or consult the
evidence-based series is expected to use independent medical judgment in
the context of individual clinical circumstances or seek out the
supervision of a qualified clinician. Cancer Care Ontario makes no
representation or guarantees of any kind whatsoever regarding their
content or use or application and disclaims any for their application or
use in any way.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Dingle B, Rumble RB, Brouwers M, Gastrointestinal Cancer Disease Site
Group. The role of gemcitabine in the treatment of cholangiocarcinoma
and gallbladder cancer. Toronto (ON): Cancer Care Ontario (CCO); 2005
Apr 26. 16 p. (DQTC-SOS advice report; no. 1). \[18 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2005 Apr 26

#### GUIDELINE DEVELOPER(S)

Program in Evidence-based Care - State/Local Government Agency
\[Non-U.S.\]

#### GUIDELINE DEVELOPER COMMENT

The Program in Evidence-based Care (PEBC) is a Province of Ontario
initiative sponsored by Cancer Care Ontario and the Ontario Ministry of
Health and Long-Term Care.

#### SOURCE(S) OF FUNDING

Cancer Care Ontario\
Ontario Ministry of Health and Long-Term Care

#### GUIDELINE COMMITTEE

Provincial Gastrointestinal Cancer Disease Site Group

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

For a current list of past and present members, please see the [Cancer
Care Ontario Web
site](http://www.cancercare.on.ca/english/toolbox/qualityguidelines/diseasesite/gastro-ebs/gastro-dsg/).

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The members of the Program in Evidence-based Care (PEBC)
Gastrointestinal Cancer Disease Site Group (DSG) declared that there
were no potential conflicts of interest related to the topic of this
Drug Quality Therapeutic Committee\'s Standing Oncology Subcommittee
(DQTC-SOS) advice report.

#### GUIDELINE STATUS

This is the current release of the guideline.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebcdqtc1f.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebcdqtc1f.pdf).

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   The role of gemcitabine in the treatment of cholangiocarcinoma and
    gallbladder cancer. Summary. Toronto (ON): Cancer Care Ontario
    (CCO), 2005 Apr 26. Various p. Electronic copies: Available in
    Portable Document Format (PDF) from the [Cancer Care Ontario Web
    site](http://www.cancercare.on.ca/pdf/pebcdqtc1s.pdf).

-   Browman GP, Levine MN, Mohide EA, Hayward RSA, Pritchard KI, Gafni
    A, et al. The practice guidelines development cycle: a conceptual
    tool for practice guidelines development and implementation. J Clin
    Oncol 1995;13(2):502-12.

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on October 26, 2006. The
information was verified by the guideline developer on November 24,
2006.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions. Please refer to the
[Copyright and Disclaimer
Statements](http://www.cancercare.on.ca/ontariocancernews/copyright.html)
posted at the Program in Evidence-Based Care section of the Cancer Care
Ontario Web site.

### DISCLAIMER

#### NGC DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008