ABSTRACT: Gallbladder carcinoma and carcinoma of the bile ducts are relatively rare cancers in the United States. These cancers are often diagnosed in an advanced stage due to their nonspecific symptomatology and until recently have been associated with a dismal prognosis. Recent advances in imaging and surgical techniques along with emerging options in palliative chemotherapy have improved the outlook in these cancers. While complete surgical resection remains the only hope of cure in both these cancers, palliative biliary decompression and chemotherapy result in substantial improvement in quality of life. Part 1 of this review, which appeared in last month’s issue, provided a relevant and comprehensive update of molecular pathology, imaging modalities, and surgical care. In part 2, we examine palliative care and systemic therapy in gallbladder and biliary tract carcinomas, as well as the use of liver transplantation in the treatment of cholangiocarcinomas. These strategies are of relevance to internists as well as oncologists caring for these patients.
Gallbladder carcinoma and cholangiocarcinoma—carcinoma of the bile ducts—are relatively rare cancers in the United States, but have long been associated with a dismal prognosis. Although complete surgical resection is the only hope for cure in both diseases, advances in diagnostic imaging techniques permit earlier diagnosis and have led to improved survival in recent years. The search for appropriate neoadjuvant or adjuvant treatments to improve survival and decrease recurrence rates is ongoing.
In the June issue of ONCOLOGY, part 1 of this two-part review summarized improvements in preoperative imaging, staging, and curative surgery. In this concluding part, we address the expanded treatment options available in terms of chemotherapy, radiation therapy, and palliative care, all of which are improving the outlook for patients diagnosed with these cancers.
Few prospective randomized trials have assessed adjuvant therapy in this rare tumor group. The available data derive from small phase II trials in which patients undergoing such treatment have been compared with historical controls.
The only phase III trial of adjuvant chemotherapy included 508 patients with resected gallbladder (n = 140), bile duct (n = 139), ampulla of Vater (n = 56), and pancreatic carcinoma (n = 173). Patients were randomized to surgery alone or with MF (mitomycin [Mutamycin]/fluorouracil [5-FU]). The MF group received mitomycin(Drug information on mitomycin), 6 mg/m2, at the time of surgery and two courses of 5-FU at 310 mg/m2 x 5 days in the postoperative period followed by oral 5-FU, 100 mg/m2/d, from postoperative week 5 until recurrence. The 5-year disease-free survival rate (for gallbladder carcinoma patients) favored adjuvant chemotherapy (20.3% vs 11.6%, P = .02), and the 5-year overall survival rate was also improved (26% vs 14.4%, P = .03). There were no significant differences in survival or disease-free survival rates in the other cancer groups.
A meta-analysis of publications concerning the role of radiation therapy in gallbladder carcinoma from 1974 to 2000 reported a slight improvement in survival after adjuvant or palliative radiotherapy. The strongest benefit was for tumors resected with only microscopic residual tissue. This report recommended an intraoperative boost of 15 Gy to the residual lesion or tumor bed with additional postoperative externalbeam radiation therapy (EBRT) of 45 to 50 Gy.
Adjuvant chemoradiation consisting of concurrent 5-FU plus EBRT in 21 resected patients with gallbladder carcinoma was associated with a 5-year survival rate of 64% in the completely resected (negative-margins) group, compared with 33% associated with surgery alone in historical controls.
Although confirmatory results from large randomized prospective trials are lacking, it is reasonable to offer patients with advanced gallbladder disease postoperative radiotherapy given the low morbidity of radiation compared with the high local recurrence rates and poor survival associated with surgery alone.Adjuvant chemotherapy with 5-FU and mitomycin may be recommended for resected gallbladder cancer.
Only 20% to 30% of patients with hilar cholangiocarcinoma are eligible for potentially curative (R0) resection. The median survival associated with an R0 resection is significantly better (22 months) than that of a palliative resection (10.7 months). Small studies suggest that neoadjuvant therapy consisting of chemotherapy, radiation, chemoradiation, or photodynamic therapy may increase rates of curative resection. However, the small size of these experiences precludes any definitive conclusion.[4,5] Cameron et al reported the Johns Hopkins experience with 96 proximal cholangiocarcinoma patients undergoing either curative or palliative surgery and 66% receiving postoperative radiotherapy. No survival advantage was associated with postoperative radiotherapy in the group undergoing curative resection; however, radiation improved survival in those undergoing palliative surgery (R1 or R2 resection).[ 6] Table 1 summarizes some of the adjuvant and neoadjuvant treatment experiences in gallbladder and cholangiocarcinoma.[1,3,4,7-10]
Liver Transplantation for Biliary Tumors
The prospect of liver transplantation as a cure for cholangiocarcinoma is appealing given encouraging results of transplantation in primary sclerosing cholangitis with incidental, small (< 1 cm) cholangiocarcinomas (Table 2).[11-16] Unfortunately, the recurrence rate is high within the first few years after transplantation.
Using life table analysis, projected 1-, 2-, and 5-year survival estimates of 72%, 48%, and 23% were reported for 207 patients who underwent liver transplantation for unresectable cholangiocarcinoma.[ 11,12] The poor long-term survival rates were secondary to high postoperative mortality and a high incidence of recurrence (51%). The majority of recurrences (85%) occurred within 2 years of transplant. Sites of recurrence were most commonly in the allograft (47%) and in the lung (30%). No prognostic markers were identified that could help with patient selection.
To decrease the rate of posttransplant recurrence, preoperative chemoradiation with 5-FU has been attempted. In a small series, 11 patients successfully completed this therapy, and at a follow-up of 44 months, only 1 had relapsed. Transplantation for hilar cholangiocarcinoma after neoadjuvant chemoradiation with infusional 5-FU and biliary brachytherapy has been evaluated in 17 patients.[ 18] Five patients had tumor progression during the neoadjuvant phase, precluding transplantation. Among the 11 who completed the protocol, 45% were alive without tumor recurrence at a median follow-up of 7.5 years.
The high risk of recurrence of cholangiocarcinoma after transplantation precludes recommending this procedure as a routine treatment for biliary tract tumors. That said, it seems reasonable to consider liver transplantation for patients with cholangiocarcinomas less than 1 cm.[11,18,19]
Malignant biliary obstruction results in much of the morbidity of biliary tract and gallbladder carcinomas. Relief of biliary obstruction palliates symptoms including jaundice and associated pruritis, pain, and weight loss.
Quality-of-life parameters have been evaluated in 50 patients undergoing endoscopic biliary drainage for malignant biliary obstruction. Weight loss and hyperbilirubinemia were strongly predictive of poor quality of life. Successful biliary drainage was associated with improvement in quality of life, although less so in those with baseline bilirubin over 13 mg/dL. Patients with malignant biliary tract obstruction attain significant improvement in emotional, cognitive, and global health scores after endoscopic stent placement.
Biliary decompression can be achieved with equivalent efficacy by operative biliary-enteric bypass or endoscopic or percutaneous stenting of the biliary tree.[22,23] Surgical decompression is recommended during an unsuccessful attempt at curative resection or in patients in whom nonsurgical decompression is not feasible. Self-expanding metallic stents produce a longer duration of patency—8 to 10 months, compared with 4 to 5 months using polyethylene endoprostheses. Survival expectations may therefore be used to guide stent selection. Reocclusion is usually secondary to tumor ingrowth or sludging.
With improvement in radiologic techniques, the results of percutaneous stenting are as good if not superior to endoscopic stenting. Percutaneous procedures may be preferable in type II-IV hilar cholangiocarcinomas, as endoscopic drainage in these cases is often difficult and results in high rates of cholangitis due to inadequate drainage.[27,28]
To improve the duration of stent patency and overall survival, adjuvant radiation and chemotherapy has been tried. In a study in 32 patients, intraluminal brachytherapy with iridium (Ir)-192 along with stent insertion was found to yield 2-year survival rates of up to 27% in those with Klatskin's tumor and up to 50% in those with carcinoma of the ampulla of Vater, along with a stent patency duration of more than 1 year. Another study in 22 patients had similar results, with mean stent patency duration of 19.5 months after treatment with Ir-192. The significance of these findings is unclear given the potential patient selection bias associated with small sample size.