Treatment of Biliary Tract Cancers
- What is the treatment for locally advanced cholangiocarcinoma?
The optimal approach to patients with locally advanced unresectable cholangiocarcinoma has not been established. The prognosis for patients with either locally unresectable or locally recurrent disease is typically measured in months. Goals of palliative therapy are relief of symptoms and improvement in quality of life, and there is no role for surgical debulking.
Liver transplantation is a potentially curative option for selected patients with hilar or intrahepatic cholangiocarcinoma. Patients with lymph node-negative, non-disseminated, locally advanced hilar cholangiocarcinomas have 5-year survival rates ranging from 25% to 42% following transplantation.52 Retrospective data suggests that neoadjuvant chemoradiation followed by liver transplantation is highly effective for selected patients with hilar cholangiocarcinoma.52 However, these results require confirmation from prospective clinical evidence. It is important to recognize that liver transplantation plays no role in the management of distal cholangiocarcinoma or gallbladder cancer.
Rarely, patients with borderline resectable intrahepatic cholangiocarcinoma will have a sufficient response to chemotherapy to permit later resection, and, in such cases, starting with chemotherapy and then restaging to evaluate resectability is appropriate.54 A single-center, retrospective analysis including 186 patients by Le Roy et al evaluated survival in patients with locally advanced, unresectable intrahepatic cholangiocarcinoma who received primary chemotherapy, followed by surgery in those with secondary resectability.54 After a median of 6 cycles of chemotherapy, 53% of patients achieved resectability and underwent surgery with curative intent. These patients had similar short- and long-term results compared to patients with initially resectable intrahepatic cholangiocarcinoma who had surgery alone, with median OS reaching 24 months.54
Ablative radiotherapy is an additional option for localized inoperable intrahepatic cholangiocarcinoma. Tao and colleagues evaluated 79 consecutive patients with inoperable intrahepatic cholangiocarcinoma treated with definitive RT.55 Median tumor size was 7.9 cm and 89% of patients received chemotherapy before RT. Median OS was 30 months and 3-year OS was 44%. Radiation dose was the single most important prognostic factor, and higher doses correlated with improved local control and OS. A biologic equivalent dose (BED) greater than 80.5 Gy was identified as an ablative dose of RT for large intrahepatic cholangiocarcinomas. The 3-year OS for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses.
Case Continued
The patient is deemed to have resectable disease and undergoes surgical resection followed by adjuvant capecitabine for 8 cycles. Unfortunately, after 1 year, follow-up imaging identifies bilateral enlarging lung nodules. Biopsy is performed and confirms metastatic cholangiocarcinoma.
- What is the treatment for metastatic BTC?
The prognosis of patients with advanced BTC is poor and OS for those undergoing supportive care alone is short. A benefit of chemotherapy over best supportive care for cholangiocarcinoma was demonstrated in an early phase 3 trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to receive either fluorouracil (FU) -based systemic chemotherapy or best supportive care. Results showed that chemotherapy significantly improved OS (6 months versus 2.5 months).56 Chemotherapy is also beneficial for patients with unresectable gallbladder cancer. In a single-center randomized study including 81 patients with unresectable gallbladder cancer, gemcitabine and oxaliplatin (GEMOX) improved progression-free survival (PFS) and OS compared to best supportive care.57 Treatment for metastatic cholangiocarcinoma and gallbladder cancer follows the same algorithm.
In 2010, cisplatin plus gemcitabine was established as a reference regimen for first-line therapy by the ABC-02 study, in which 410 patients with locally advanced or metastatic bile duct, gallbladder, or ampullary cancer were randomly assigned to 6 courses of cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2 on days 1 and 8, every 21 days) or gemcitabine alone (1000 mg/m2 days 1, 8, 15, every 28 days).58 OS was significantly greater with combination therapy (11.7 versus 8.1 months), and PFS also favored the combination arm (8 versus 5 months). Toxicity was comparable in both groups, with the exception of significantly higher rates of grade 3 or 4 neutropenia with gemcitabine plus cisplatin (25% versus 17%), and higher rates of grade 3 or 4 abnormal liver function with gemcitabine alone (27% versus 17%). Most quality-of-life scales showed a trend favoring combined therapy.58 A smaller, identically designed Japanese phase 3 randomized trial achieved similar results, demonstrating greater OS with cisplatin plus gemcitabine compared to gemcitabine alone (11.2 versus 7.7 months).59
The gemcitabine plus cisplatin combination has not been directly compared with other gemcitabine combinations in phase 3 trials. A pooled analysis of 104 trials of a variety of chemotherapy regimens in advanced biliary cancer concluded that the gemcitabine plus cisplatin regimen offered the highest rates of objective response and tumor control compared with either gemcitabine-free or cisplatin-free regimens.60 However, this did not translate into significant benefit in terms of either time to tumor progression or median OS. It is important to note that this analysis did not include results of the subsequent ABC-02 trial.
There is no standard treatment for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. There are no completed prospective phase 3 trials supporting the use of second-line chemotherapy after failure of first-line chemotherapy in BTC, and the selection of candidates for second-line therapy as well as the optimal regimen are not established.61 The ongoing phase 2 multicenter ABC-06 trial is evaluating oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX) versus best supportive care for second-line therapy. In a systematic review including 23 studies (14 phase 2 clinical trials and 9 retrospective studies) with 761 patients with BTC, the median OS was 7.2 months.
The optimal selection of candidates for second-line chemotherapy is not established. Two independent studies suggest that patients who have a good performance status (0 or 1), disease control with the first-line chemotherapy, low CA 19-9 level, and possibly previous surgery on their primary tumor, have the longest survival with second-line chemotherapy. However, whether these characteristics predict for chemotherapy responsiveness or more favorable biologic behavior is not clear.62,63 No particular regimen has proved superior to any other, and the choice of second-line regimen remains empiric.
For patients with adequate performance status, examples of other conventional chemotherapy regimens with demonstrated activity that could be considered for second-line therapy include: FOLFOX or capecitabine, gemcitabine plus capecitabine, capecitabine plus cisplatin, or irinotecan plus short-term infusional FU and leucovorin (FOLFIRI) with or without bevacizumab.64 For selected patients, second-line molecularly targeted therapy using erlotinib plus bevacizumab may be considered. However, this regimen is very costly.64 Examples of other regimens with demonstrated activity in phase 2 trials include GEMOX, gemcitabine plus fluoropyrimidine, and fluoropyrimidine plus oxaliplatin or cisplatin.64
There is promising data from studies of targeted therapy for specific molecular subgroups. A recent phase 2 trial evaluated the activity of BGJ398, an orally bioavailable, selective, ATP-competitive pan inhibitor of human fibroblast growth factor receptor (FGFR) kinase, in patients with FGFR-altered advanced cholangiocarcinoma.65 The overall response rate was 14.8% (18.8% FGFR2 fusions only) and disease control rate was 75.4% (83.3% FGFR2 fusions only). All responsive tumors contained FGFR2 fusions. Adverse events were manageable, and grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%). Those included hyperphosphatemia, stomatitis, and palmar-plantar erythrodysesthesia. Javle and colleagues also identified HER2/neu blockade as a promising treatment strategy for gallbladder cancer patients with this gene amplification.66 This retrospective analysis included 9 patients with gallbladder cancer and 5 patients with cholangiocarcinoma who received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab). In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in 8 cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu–directed therapy. Median duration of response was 40 weeks. The cholangiocarcinoma cases treated in this series had no radiological responses despite HER2/neu mutations or amplification.
