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.
