Cancer gallbladder; treatment of advance and unresectable disease.

Patients with locally advanced, unresectable gallbladder carcinoma may present with symptoms of jaundice, pain, and bowel obstruction. These patients have a limited life expectancy, on the order of months, especially in the setting of liver and/or peritoneal dissemination.

• The treatment of locally advanced, unresectable gallbladder carcinoma is palliation aimed at relief of pain, jaundice, and bowel obstruction, along with prolongation of life.

• Patients who have pain from local growth may benefit from radiation therapy with or without concomitant chemotherapy.
  
• Although biliary or intestinal bypass can be considered, a percutaneous or endoscopic approach may be preferred, given the limited median survival in patients with advanced disease (generally, less than six months).

Recurrence
In a recent retrospective review of the patterns of initial disease recurrence after potentially curative surgical resection, Jarnagin et al. followed 80 patients with gallbladder carcinoma and compared them to 76 patients with hilar cholangiocarcinoma.

• The median time to disease recurrence was shorter for gallbladder carcinoma patients (11.5 months) compared to patients with hilar cholangiocarcinoma (20.3 months).
• At a median follow-up of 24 months, 68% of patients with hilar cholangiocarcinoma and 66% of patients with gallbladder carcinoma suffered disease recurrence.
• The site of initial disease recurrence was locoregional in only 15% of patients with gallbladder carcinoma compared to 59% of patients with hilar cholangiocarcinoma.
• In contrast, 85% of patients with gallbladder carcinoma had a distant (+/−locoregional) site as their initial site of failure compared to 41% of patients with hilar cholangiocarcinoma.
• This study provides considerable insight into the clinical behavior of these malignancies and suggests that in the case of gallbladder carcinoma, improvements in survival are most likely to be achieved with more effective systemic therapies as opposed to adjuvant treatment such as radiation therapy designed to achieve better locoregional control.

Radiation therapy

External beam radiation(EBRT) may be considered for palliative management of patients with locally advanced disease, particularly if there is no evidence of metastatic disease, and patients are symptomatic. At the time of exploration, the margins of unresectable and/or residual disease are often marked with radiopaque clips to facilitate treatment planning.

• Hanna and Rider reported on 51 patients with gallbladder carcinoma from the Princess Margaret Hospital, 35 of whom underwent a potentially curative surgical resection and EBRT.
• There was a survival advantage for those patients who received adjuvant EBRT in addition to surgery compared with those who had surgery alone.
• Several other small, retrospective series consisting of heterogeneous groups of patients with diverse treatment schema and follow up criteria have been published, making definitive conclusions about the potential benefits of adjuvant EBRT difficult.
• Most recently, Kresl et al. published their retrospective analysis of adjuvant EBRT with concurrent 5-FU after curative surgical resection in 21 patients with gallbladder cancer treated at the Mayo Clinic from 1985 through 1997. Patients with a margin-negative (R0) resection followed by adjuvant EBRT plus 5-FU had a favorable 5-year survival rate of 64%.
• However, similar to the findings of Jarnagin et al. [58], 67% of the patients suffered distant failure, emphasizing the need for more effective adjuvant chemotherapy for this disease.

Intraoperative radiation therapy (IORT) has been advocated as a means to deliver high-dose, small-field therapy directly to the tumor bed without the dose limitations associated with EBRT. Todoroki et al. have reported the most substantial experience with IORT in 85 patients with AJCC stage IV gallbladder cancer who underwent aggressive surgical resection with or without IORT at a mean dose of 21 Gy.

• Fortyseven patients in total received some form of radiation therapy (EBRT and/or IORT).
• The local control rate was significantly higher after adjuvant radiotherapy (59%) than after resection alone (36%).
• Moreover, the 5-year survival rate was significantly higher after adjuvant radiotherapy (9%) than after resection alone (3%), with the most pronounced improvement in 5-year survival rate (17%) in patients with only microscopic residual disease (R1 resection).

The role of radiation therapy for the palliation of symptoms such as jaundice, pain, and pruritus in patients with unresectable disease is difficult to ascertain as published studies consist of small numbers of patients with the significant confounding variable that most patients also underwent a biliary drainage procedure.

Chemotherapy

Most published studies concerning the role of chemotherapy in patients with locally advanced or metastatic gallbladder carcinoma are limited by the small numbers of patients and by the inclusion of patients with biliary tract cancers.

• Unfortunately, no single chemotherapeutic agent or combination of agents has been identified to be effective in the treatment of this disease .
• Though overall response rates range as high as 64%, complete responses are rare and median overall survival rates range from only 20 weeks to 15 months.
• 5-fluoruracil (5-FU), administered either alone or in combination, is the most extensively studied chemotherapeutic agent for this disease.
• In a prospective, randomized study of 53 patients with advanced gallbladder cancer treated with oral 5-FU alone or in combinationwith either streptozocin or methyl-CCNU, objective response rates ranged from 5 to 12% in the three treatment arms.
• 5-FU administered in combination with doxorubicin and mitomycin C (FAM) or in combination with cisplatin and epirubicin (CEF) has yielded response rates of 8% and 33%, respectively.
• Better response rates have been published in patients treated with combinations of 5-FU with hydroxyurea (30%) or interferon alpha-2b (34%).

Other chemotherapeutic agents have exhibited variable success in the treatment of advanced gallbladder cancer. Cisplatin, mitomycin C, paclitaxel, and CPT-11 have produced response rates of 10% or less as single agents.

• In contrast, four of eight patients with gallbladder carcinoma treated with single-agent oral capecitabine had either a complete (n =2) or partial (n =2) response.
• Several case reports have shown that gemcitabine is active in the treatment of patients with gallbladder carcinoma.
• Accordingly, several phase II studies of gemcitabine in combination with other agents have subsequently been reported.
• Gemcitabine in combination with cisplatin has yielded response rates of 36 to 64%; in combination with docetaxel yielded a response rate of only 9%; and in combination with 5-FU has produced response rates of 9 to 33%.
• Based on these studies, it appears that gemcitabine is an important component of the systemic therapy of gallbladder carcinoma, but additional studies of gemcitabine in combination with other agents are warranted, as the survival benefit with existing regimens is modest at best.

Hepatic arterial infusion chemotherapy has been studied in a few patients with locally unresectable gallbladder cancer.

• Partial response rates of up to 60% have been reported, but the median duration of response was only 3 months and all patients developed progressive disease.
• The median overall survival rates of 12 to 14 months in these studies is comparable to that achieved with intravenous chemotherapy, providing little impetus to recommend this more complicated mode of drug delivery.

Targeted therapy —

Early data suggest possible benefit from blockade of the epidermal growth factor receptor (EGFR) by the oral tyrosine kinase inhibitor erlotinib.

• In one study, 42 patients with advanced biliary cancer (not stratified according to primary site), 57 percent of whom had received prior chemotherapy, received erlotinib (150 mg daily).
• There were three partial responses (two with documented expression of EGFR) and seven additional patients remained progression-free at six months.
• All responding patients had mile (grade 1 or 2) skin toxicity.

• Further experience with this drug is needed, particularly combined with cytotoxic chemotherapy.

Palliative surgery

For patients with unresectable disease detected radiographically or laparoscopically, biliary drainage is best achieved by endoscopic or percutaneous means.

• If unresectable disease is discovered at the time of laparotomy, a biliary bypass (hepaticojejunostomy or segment III bypass) can be performed.
• However, in a prospective study of 21 consecutive patients with unresectable gallbladder cancer who underwent a segment III bypass, six (29%) suffered complications; three (14.3%) patients had bile leaks, and three patients died as a result of the procedure.
• The median survival of these 21 patients was only 20 weeks, and all but three patients died within 32 weeks of the surgery.
• Given this limited life expectancy, patients with unresectable gallbladder cancer and biliary obstruction are best palliated by percutaneous or endoscopic stenting.

Intestinal bypass offers durable relief of intestinal obstruction, though there are reports of excellent palliation of malignant duodenal obstruction by the endoscopic placement of expandable metal Wallstents.