The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer : A systematic review

1London Regional Cancer Program, Department of Oncology, University of Western Ontario, London, Ontario; 2Cancer Care Ontario’s Program in Evidence-Based Care, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario; 3See Appendix 1 Correspondence: Mr R Bryan Rumble, McMaster University, 50 Main Street East, Room 319, 3rd floor, Hamilton, Ontario L8N 1E9. Telephone 905-525-9140 ext 22202, fax 905-522-7681, e-mail rumbleb@mcmaster.ca Received for publication June 5, 2005. Accepted June 17, 2005 BH Dingle, RB Rumble, MC Brouwers, Cancer Care Ontario’s Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: A systematic review. Can J Gastroenterol 2005;19(12):711-716.

The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: A systematic review BACKGROUND: Cholangiocarcinoma and gallbladder cancer are difficult to treat curatively.The treatment of choice is surgery, dependent on detection at a resectable stage.No chemotherapy or radiotherapy options have shown substantial activity.Gemcitabine has demonstrated response in similar cancers.Considering the lack of treatment options for cholangiocarcinoma and gallbladder cancer, a systematic review of the evidence on gemcitabine use for these indications was performed.OBJECTIVE: To perform a systematic review to evaluate the role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer.

METHODS:
The MEDLINE database was searched (1996 to March 2005) using the medical subject headings 'gemcitabine' and 'gallbladder neoplasms' with results limited to English only.Proceedings from the 1998 to 2004 meetings of the American Society of Clinical Oncology, including the 2004 Gastrointestinal Cancers Symposium, were searched for relevant abstracts.The Canadian Medical Association infobase and the National Guidelines Clearinghouse were also searched for practice guideline reports.Reports were selected and reviewed by two reviewers, and the reference lists from those were searched for additional trials.RESULTS: A total of 13 single-arm phase II trial reports were obtained.

CONCLUSIONS:
In appropriate patients with gallbladder cancer or cholangiocarcinoma, surgery offers the best chance for survival and should remain the first treatment of choice.For patients not considered candidates for surgery, but willing and able to tolerate chemotherapy alone or in combination with a fluoropyrimidine (such as 5-fluorouracil or capecitabine), gemcitabine appears to be a reasonable alternative to best supportive care, although this conclusion has not been confirmed with a randomized controlled trial.Pour les patients qui ne peuvent être candidats à une opération mais qui sont prêts à tolérer une chimiothérapie seule ou en association avec de la fluoropyrimidine (comme du 5-fluorouracil ou de la capécitabine) et en mesure de la faire, la gemcitabine semble constituer une solution raisonnable aux meilleurs soins de soutien, même si cette conclusion n'a pas été étayée par un essai aléatoire et contrôlé.
C ancers of the biliary tree, including cholangiocarcinoma and gallbladder cancer, are difficult to treat with curative intent for several reasons.First, they are rare in the population (1), making adequate accrual into randomized controlled trials (RCTs) difficult and time-consuming; second, many patients present with unresectable disease and are eligible for palliative treatment only (1); and third, no chemotherapy or radiotherapy options tested to date have shown any substantial activity (1).Currently, the treatment of choice for these cancers is surgery, but surgery is dependent on the cancer being detected at an early, resectable stage.Recently, the role of radiation therapy in combination with chemical radiosensitizers has been investigated (1).
In Canada, gallbladder cancer represented 0.28% (381 of 134,413) of all new cancers in 2000 and 0.41% (259 of 62,672) of all cancer deaths (2).Gallbladder cancer affected female patients at 2.3 times the rate for male patients for both incidence and mortality (2).Incidence, mortality and sex-specific data were not available for cholangiocarcinoma.
Gemcitabine is a newer drug available to Ontario clinicians.It has demonstrated a treatment response in pancreatic cancer patients (3,4) and is also indicated for the treatment of non-small cell lung cancer (4).Gemcitabine is an intravenous drug that is metabolized within tumour cells by nucleoside kinases to the active gemcitabine diphosphate and gemcitabine triphosphate nucleosides.These gemcitabine nucleosides inhibit DNA synthesis via two processes.In the first, gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing reactions that generate the deoxynucleoside triphosphates for DNA synthesis.In the second, gemcitabine triphosphate competes with deoxycytidine 5'-triphosphate for incorporation into DNA.By using these two mechanisms, gemcitabine induces a programmed cell death response by blocking the progression of dividing cells through the G1/S phase boundary (4).
Considering the demonstrated treatment response of gemcitabine in similar cancers, the lack of effective alternative treatment options for cholangiocarcinoma and gallbladder cancer, and the interest by some Ontario clinicians to have access to this drug, the Gastrointestinal Cancer Disease Site Group (DSG) of Cancer Care Ontario's Program in Evidence-Based Care (PEBC) decided to conduct a systematic review of the evidence to answer the following clinical question: what is the role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer?The outcomes of interest included overall response rates and survival, adverse effects and quality of life.This systematic review served as the basis for a clinical practice guideline.

METHODS
The present report, produced by the PEBC's gastrointestinal cancer DSG, is a convenient and up-to-date source of the best available evidence on the role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer developed through a systematic review of the available evidence.Members of the DSG disclosed any potential conflicts of interest.The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Literature search strategy
The MEDLINE database was searched from 1996 to the second week of March, 2005.The medical subject headings 'gemcitabine' and 'gallbladder neoplasms' were combined and results were limited to English only.In addition, conference proceedings from the 1998 to 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/index.asp)were also searched for existing evidence-based practice guidelines.An additional article not found in the literature search, because it was too recent to be indexed, was obtained from a Gastrointestinal Cancer DSG member.
Relevant articles and abstracts were selected and read by two reviewers, and the reference lists from those sources were then 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. RCTs comparing gemcitabine, either alone or in combination, with best supportive care or other therapy for cholangiocarcinoma or gallbladder cancer; and 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
Letters and editorials were not eligible.

Synthesizing the evidence
None of the trials obtained were RCTs; therefore, no pooling of outcome data was possible.

Gemcitabine monotherapy
Efficacy outcomes: Three single-arm, phase II trials investigating gemcitabine monotherapy were obtained (Table 1) (5-7).The doses used appear in Appendix 2. Response rates ranged from 30% in two trials (6,7) to 36% (5); however, none of the patients across those trials (n=78) experienced a complete response.Median survival rates reported ranged from a low of 30 weeks (5) to a high of 56 weeks (7).One-year survival rates ranged from 16% (5) to 57% (7).Adverse effects: Adverse effects observed in the trials of gemcitabine monotherapy are described as follows: one trial (5) reported no grade 3/grade 4 adverse effects and one trial (7) reported no grade 4 adverse effects.Two trials reported either grade 3 or grade 4 neutropenia (6,7).At least one trial reported the following grade 3/grade 4 effects: anemia (6); nausea (6); flu-like symptoms (6); hemolytic uremic syndrome (6); and anorexia (7).Generally, the gemcitabine monotherapy trials reported that any adverse effects observed were mild and manageable.See Appendix 3 for adverse effects tables.Quality of life: None of the trials on gemcitabine monotherapy reported data on quality of life.

DISCUSSION
The most effective treatment for cancer of the gallbladder is surgical resection of the primary tumour along with any local spread (1), but surgery is dependent on the patient presenting at an early, resectable stage.Curative resection of cholangiocarcinoma is more complex and is dependent on the site and extent of the tumour (1).Five-year survival after the surgical resection of stage I gallbladder cancer should be greater than 85% (1), but drops to 25%, 10% and 2% for stage II, III and IV tumours, respectively (1).For patients with resectable cholangiocarcinoma, five-year survival rates range from 35% to 45% (1).There  is no generally accepted standard chemotherapy for advanced, nonresectable 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% (1).In past phase II studies, response rates for the use of fluoropyrimidines in this population ranged from 10% to 24% (1).Gemcitabine, either alone or in combination with other commonly used drugs such as fluoropyrimidines (10,13,17) or cisplatin, (8,12,15) 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 (11) and carboplatin ( 16) 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 (SWOG-S0202 and NCI-6254).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 exceeds 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 than 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.Knox et al (17), in their most recent article, stated that a previous retrospective review of gemcitabine and continuous infusion 5-FU (18) 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.

CONCLUSIONS Recommendations
See Appendix 2 for recommended regimens and doses.
• 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 the chemotherapy, gemcitabine, either alone or in combination with a fluoropyrimidine (such as 5-FU or capecitabine), appears to be a reasonable alternative to best supportive care, although this conclusion has not been confirmed with an RCT.
• Patients should be encouraged to enroll in RCTs comparing promising new treatments, such as gemcitabine in combination with a fluoropyrimidine, against other treatments with proven response.

Future research
Patients with cancers of the biliary tree should be encouraged to enroll in clinical trials designed to assess the efficacy, adverse effects and quality of life scores of gemcitabine, either alone or in combination, compared with other treatments with proven response.

Related clinical practice guidelines:
The PEBC Practice Guideline Report #2-10: Use of gemcitabine in the treatment of advanced pancreatic carcinoma.

CONFLICTS OF INTEREST:
The authors declared no conflicts of interest related to the topic of this report.

Combination therapy regimens
Carraro et al (8), 2001 1000 mg/m 2 gemcitabine as a 30 min infusion, followed by 30 mg/m 2 cisplatin IV bolus injection, administered on days 1, 8 and 15 of each cycle, repeated every 28 days Kuhn et al (9), 2002 1000 mg/m 2 gemcitabine, followed by 35 mg/m 2 docetaxel once a week, for three weeks, followed by one week of rest Alberts et al (10), 2005 1000 mg/m 2 gemcitabine IV for 30 min, followed by 25 mg/m 2 leucovorin calcium IV push, followed immediately by 600 mg/m 2 5-FU IV push on days 1, 8 and 15, repeated every four weeks André et al (11), 2004 1000 mg/m 2 gemcitabine as a 10 mg/m 2 /min infusion on day 1, followed by a 2 h infusion of 100 mg/m 2 oxaliplatin on day 2, every two weeks Doval et al (12), 2004 1000 mg/m 2 gemcitabine 30 min to 60 min infusion and 70 mg/m 2 cisplatin 2 h infusion were given on day 1, 1000 mg/m 2 gemcitabine alone was given on day 8, in a 21 day cycle Hsu et al (13), 2004 800 mg/m 2 gemcitabine IV infusion for 30 min followed by 2000 mg/m 2 5-FU and 3000 mg/m 2 leucovorin IV for 24 h on days 1, Treatment of cholangiocarcinoma and gallbladder cancer Can J Gastroenterol Vol 19 No 12 December 2005 713

8 and 15 ,
repeated every four weeks Kornek et al(14), 2004 2000 mg/m 2 gemcitabine on days 1 and 15, with 8 mg/m 2 MMC on day 1 only, repeated every four weeks Reyes-Vidal et al(15), 1250 mg/m 2 gemcitabine and 35 mg/m 2 cisplatin on days 1 and 8, every 21 days, for a total of six cycles 2004 Tan et al (16), 2004 1000 mg/m 2 gemcitabine IV over 30 min on days 1 and 8, with carboplatin at area under the curve 5 IV on day 1 only, of a 21 day cycle Knox et al (17), 2005 1000 mg/m 2 gemcitabine IV over 30 min on days 1 and 8, with 650 mg/m 2 capecitabine orally twice a day for 14 days, three-week cycle; treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent 5-FU 5-fluorouracil; IV Intravenously; MMC Mitomycin-c Continued on next page

TABLE 1
*(Evaluated response) and [evaluated toxicity].5-FU/LV 5-fluorouracil/leucovorin; CAPE Capecitabine; CARBO Carboplatin; CIS Cisplatin; CR Complete response; DOC Docetaxel; EV Evaluated; GEM Gemcitabine; L-OHP Oxaliplatin; MMC Mitomycin-c; NR Not reported; PR Partial response (7) Gastrointestinal Cancer Disease Site Group would like to thank Dr B Dingle, Mr R Rumble and Dr M Brouwers for taking the lead in drafting and revising this document.The Gastrointestinal Cancer Disease Site Group would also like to thank Dr Jennifer Knox for commenting on an early draft of this report.The Program in Evidence-Based Care is supported by Cancer Care Ontario and the Ministry of Health and Long-Term Care.Gallardo et al(5), 2001 1000 mg/m 2 gemcitabine IV for 30 min/week, three weeks of every four weeks Kubicka et al(6), 2001 1000 mg/m 2 gemcitabine IV for 30 min/week, three weeks of every four weeks Tsavaris et al(7), 2004 800 mg/m 2 gemcitabine IV for 30 min/week, without cessation, until severe toxicity, disease progression or patient refusal arose