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. Adjuvant Treatment Gallbladder Carcinoma
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).[1] Patients were randomized to surgery alone or with MF (mitomycin [Mutamycin]/fluorouracil [5-FU]). The MF group received mitomycin, 6 mg/m2, at the time of surgery and two courses of 5-FU at 310 mg/m2 * 5 days in the postopera- tive 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.[2] 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.[3] 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.Adju- vant chemotherapy with 5-FU and mitomycin may be recommended for resected gallbladder cancer.[1] Cholangiocarcinoma
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).[4] 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.[17] 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] Palliative Treatment Biliary Decompression
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.[20] 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.[21] 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.[ 24] Survival expectations may therefore be used to guide stent selection. Reocclusion is usually secondary to tumor ingrowth or sludging.[25] With improvement in radiologic techniques, the results of percutaneous stenting are as good if not superior to endoscopic stenting.[26] 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.[29] Another study in 22 patients had similar results, with mean stent patency duration of 19.5 months after treatment with Ir-192.[30] The significance of these findings is unclear given the potential patient selection bias associated with small sample size. Palliative Chemotherapy Patients with cholangiocarcinoma or gallbladder carcinoma typically present late in the course of their disease and often are not candidates for curative surgical resection. In cases where surgical intervention is not warranted, palliative chemotherapy has been used to diminish symptoms and possibly to extend survival. Only one large randomized trial has addressed the role of palliative chemotherapy in advanced biliary tract cancer. Glimelius et al randomized patients with pancreatic cancer and biliary tract cancer to a regimen of 5-FU/leucovorin with or without etoposide, or best supportive care, and evaluated these strategies for disease response and quality-of-life indicators. Of 90 enrolled patients, 37 had advanced biliary tract carcinoma. Marked although short-term improvements in survival (6.5 vs 2.5 mo) and quality of life (measured with the European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30 instrument) were noted in the treatment group, establishing a role for palliative treatment in unresectable disease.[31,32] Several phase I and II trials, as well as numerous case and series reports, have assessed the efficacy and toxicity profiles of various chemotherapy regimens in the palliative treatment of biliary tract tumors. A variety of single-agent and multiagent chemotherapy regimens have yielded modest results in palliating patients with advanced carcinomas. Response rates have ranged from 0% to 47%. No consensus has been reached regarding standard of care. Many drugs including 5-FU/leucovorin, cisplatin, oxaliplatin (Eloxatin), carboplatin (Paraplatin), mitomycin C (Mutamycin), doxorubicin, interferon- alfa 2b (Intron A), gemcitabine (Gemzar), epirubicin (Ellence), capecitabine (Xeloda), irinotecan (Camptosar), and docetaxel (Taxotere) continue to be evaluated alone and in combination for the treatment of advanced biliary cancer. While the results of these phase II trials do not permit conclusive recommendations for a particular regimen, they do indicate that progression of advanced carcinoma of the biliary tract can in many cases be temporarily controlled. Partial responses consistently ranging from 10% to 30% and disease stabilization rates from 10% to 50%, as well as improving median time to progression and median overall survival time, indicate that investigation of palliative treatment warrants continued attention. This section summarizes recent phase I and II trials in the management of biliary tract tumors. Small sample sizes in each trial and the small number of trials preclude the development of statistically significant findings in cross-study analyses. Furthermore, studies seldom examine identical dosing and delivery schedules, making cross-study comparison difficult. However, analyzing the results of these trials can provide guidance in the clinical management of patients and suggest new avenues for investigation. 5-FU/Leucovorin
Either in combination or as a single agent, 5-FU has been used in the management of biliary carcinomas for almost 30 years. Single-agent studies have met with variable success. From 1974 to 1994, four small studies (enrolling between 7 and 30 patients) investigated the efficacy of singleagent 5-FU. Response rates ranged from 0% to 24% in a total of 78 patients.[31] Table 3 summarizes the results of the Glimelius et al randomized trial and three additional 5-FU/leucovorin trials.[32-35] Response rates in these trials appear better than those reported for 5-FU alone.[32] The toxicity of 5-FU/leucovorin regimens is tolerable and easily managed. Grade 3/4 toxicities have included mucositis, diarrhea, hematologic toxicity, asthenia, and abdominal pain. 5-FU Combination Regimens
Given the poor responses with 5-FU/leucovorin alone, investigators have evaluated 5-FU-based combinations in a number of phase I and II clinical trials. These trials are summarized in Table 4.[36-47] Outcomes have been mixed, with partial response rates ranging between 0% and 64% and disease stabilization rates from 0% to 50%. Complete responses have been rare. Reported median time to progression ranges from 3 to 10 months, while reported median survival ranges from 5 to 32 months.
  • 5-FU and Mitomycin- Singleagent mitomycin has been used in several trials, with response rates ranging from 0% to 47%.[31] The FAM regimen (5-FU, doxorubicin [Adriamycin], mitomycin) demonstrated a disease control rate (complete and partial responses plus disease stabilization) of 81%.[36] Unfortunately, other mitomycin-based trials have shown unacceptable toxicity. A trial of mitomycin, 10 mg/m2 every 8 weeks, together with weekly 5-FU at 2,600 mg/m2 plus leucovorin at 150 mg/m2 was stopped after treatment-related deaths exceeded 10% in the first 25 patients.[48] Given the potential toxicity of mitomycin and the availability of other agents, further investigation of mitomycin regimens is probably not warranted.
  • 5-FU and Platinum- Cisplatin has minimal activity as a single agent against biliary tract carcinomas.[31] The combination of 5-FU and cisplatin has been assessed in several trials with variable success. An over- all response rate of 24% was attained in a 25-patient trial evaluating 5-FU, 1,000 mg/m2 intravenous infusion daily for 5 days, plus a 1-hour infusion of cisplatin, 100 mg/m2 on day 2.[37] The PIAF regimen (cisplatin, interferon alfa-2b, doxorubicin, 5-FU) produced response rates of 35% and 9.5% in 19 gallbladder carcinoma patients and 22 cholangiocarcinoma patients, respectively. Although the median survival of 14 months was encouraging, the significant toxicity profile of PIAF, which included grade 3/4 neutropenia (41%), nausea and vomiting (34%), thrombocytopenia (20%), and anemia (15%), precludes future use.[38] In addition, it is impossible to discern the contribution, if any, of interferon in this regimen.
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    We would like to acknowledge Dr. Warren Enker, chief of colorectal surgery at Beth Israel Medical Center and professor of surgery at the Albert Einstein College of Medicine in New York, and Dr. Ronald Chamberlain, chief of hepatobiliary and pancreatic surgery at Beth Israel and assistant professor of surgery at the Albert Einstein College of Medicine, for their critical review of this manuscript.