While current guidelines have not established a standard first-line chemotherapeutic regimen for unresectable cholangiocarcinoma, recent publications have shed light on potential regimens. A recent pooled analysis of 104 trials representing 2810 patients with advanced biliary tract cancers treated with chemotherapy in the last 35 years demonstrated highest response rates and tumor control rates with combination gemcitabine and platinum regimens.9
Gemcitabine and cisplatin showed 30%–50% response rates compared to 20%–40% with other agents. However, overall survival was not significantly impacted.
The ABC-02 trial compared doublet therapy with gemcitabine and cisplatin to gemcitabine as a single agent in 410 patients with locally advanced or metastatic biliary tract cancer.8
In this trial, 59% (241 patients) had bile duct tumors, but the particular site of disease within the bile duct was not specified. After a median follow-up of 8.2 months, the combination group had a significantly improved OS (11.7 vs 8.1 months).
While gemcitabine/cisplatin has now become the standard regimen for cholangiocarcinoma, alternatives need to be explored for patient populations that are not appropriate candidates for this combination therapy. Moreover, recent data in pancreatic cancer suggest that genetic variations of gemcitabine metabolic genes (such as HENT1) may predict for nonresponsiveness to gemcitabine. Under such circumstances, fluoropyrimidines may be more appropriate.10,11
Further data are needed to identify the effects of genetic polymorphisms in the outcomes of cholangiocarcinoma patients as well.
Analysis of our patient population from the past 5 years also suggests that the combination of gemcitabine and cisplatin is an effective option for maintaining disease control in patients with unresectable intrahepatic or hilar cholangiocarcinoma. The majority of patients (73%) had a partial response or stable disease with this regimen. Duration of response was 8.1 months, which was similar to the 8 month progression-free survival seen in the ABC-02 trial with this regimen.8
Also, median overall survival was substantial at 15.2 months, which compares favorably with historical literature.12
Of note, patients referred to our center who were initially diagnosed at other centers as having an unknown primary tumor trended toward a decrease in tumor control rate and had significantly shorter duration of response and overall survival. This inferior outcome may be the result of a prolonged workup, as these patients typically undergo a series of tests that can lead to delays before initiation of appropriate therapy. Additionally, further delay may occur during transfer of care from one institution to another when the staging workup is repeated. These observations highlight the importance of quickly identifying these tumors and promptly transferring patients to a center experienced in treating biliary tract cancers.
Another subset of patients that demonstrated inferior outcomes included patients who had received prior chemoradiotherapy. While this consisted of only 5 patients and should be interpreted with caution, the finding is consistent with a recent phase III trial in which pancreatic cancer patients who had received induction chemoradiotherapy followed by chemotherapy exhibited a shorter overall survival compared with patients who received chemotherapy alone.13
In contrast, improved overall survival has been achieved in pancreatic cancer patients by delivering consolidation chemoradiotherapy after induction chemotherapy compared to chemotherapy alone.14
In this setting, response to chemotherapy may identify patients who will benefit further from chemoradiotherapy. These pancreatic cancer studies emphasize the importance of the timing of treatment in addition to the modality of therapy. These principles need to be further explored to determine if our current institutional practice of consolidative chemoradiotherapy provides clinical benefits in cholangiocarcinoma as well as pancreatic cancer.
Our results are remarkable for the broad range of survival times observed, from less than 3 months to longer than 4.5 years. There are a small number of patients with continued response to their initial treatment regimen after almost 4 years of therapy. It is intriguing that some patients respond so well to therapy for a disease associated with such a dismal prognosis. Additional research is warranted to tease out the genetic backgrounds and clinical characteristics of the long-term responders as part of a strategy to explore potential avenues toward individualized approaches to therapy.
Another interesting finding from this retrospective study is that capecitabine/oxaliplatin was an alternative regimen that showed tumor control and overall survival rates similar to those seen with the gemcitabine/cisplatin regimen. Few data have been published regarding the use of this regimen in cholangiocarcinoma. A prospective phase II study published in 2008 evaluated capecitabine/oxaliplatin as first-line therapy in advanced biliary tract adenocarcinoma.15
The authors concluded that capecitabine/oxaliplatin was an active treatment for extrahepatic cholangiocarcinoma and gall bladder cancer but may be less effective in intrahepatic cholangiocarcinoma. They reported that no patients in the intrahepatic group of 18 patients had an objective response to therapy and 33% exhibited stable disease. In our study, of the 14 patients who received capecitabine/oxaliplatin, 13 had intrahepatic cholangiocarcinoma. Of these 13 patients, 2 patients (15%) had a partial response to capecitabine/oxaliplatin, and an additional 7 patients (54%) had stable disease.
In our study population, this regimen was well tolerated, with only 3 patients (21%) discontinuing therapy due to toxicity. This regimen could emerge as an alternative for patients unable to tolerate cisplatin. For example, in our analysis, 11% of patients discontinued gemcitabine/cisplatin for elevations in creatinine, so capecitabine/oxaliplatin could be explored in patients with mild baseline kidney disease as an alternative first-line regimen. However, duration of response may be less with capecitabine/oxaliplatin, so further investigation is needed before routinely recommending this regimen.
While chemotherapy regimen recommendations for cholangiocarcinoma are not site-specific because of the small numbers of patients with this disease, efforts are being made to identify which patients are more likely to respond to different treatment regimens. Physicians from Memorial Sloan-Kettering Cancer Center (MSKCC) recently published their experience in treating patients with intrahepatic cholangiocarcinoma since 1990, including 115 patients with unresectable disease who received chemotherapy.12
Compared to the first 10 years of the study (1990–1999), when the majority of patients were treated with 5-FU and leucovorin, the median survival for unresectable intrahepatic cholangiocarcinoma significantly improved from 6 to 15 months. Regimens used most frequently in the more recent part of the study (2000–2006) included gemcitabine and irinotecan. Our study similarly attempted to separate out a subgroup of the cholangiocarcinoma population and identify regimens that might be most effective for intrahepatic or hilar tumors. Our data showed comparable survival to the MSKCC data, with a median overall survival of more than 16 months in the intrahepatic group.12
It is important to recognize the limitations inherent in performing any retrospective study. As most patients received gemcitabine/cisplatin, the treatment groups were not evenly matched for comparison. A high proportion of patients received some of their chemotherapy at outside institutions and were eliminated from our analysis to ensure accuracy of the data. Because of these strict inclusion criteria and the rare nature of the disease, only 85 patients were eligible for analysis. While this is a relatively large group, comparable to other studies published in this patient population, the sample size limits conclusions that may be drawn from the data, particularly when analyzing subgroups of the population.
Another limitation is that radiologic assessment of response can be challenging in hilar cholangiocarcinoma, particularly in those with a diffuse/infiltrative disease pattern. Finally, the inclusion of cholangiocarcinomas of both hilar and intrahepatic origin may obscure the data regarding the response of either tumor type.
The results and conclusions drawn from our study are strengthened by the fact that all patients received standard doses of chemotherapy as per institutional template guidelines. Additionally, follow-up high-resolution radiologic and clinical data were complete and reviewed by a multidisciplinary team. Moreover, our results are comparable with those from other tertiary institutions.
One future direction to consider is the incorporation of biologic therapy into chemotherapy regimens. A retrospective review by Yoshikawa examined the immunohistochemical expression of growth factor receptors on cholangiocarcinoma tumor cells.16
This study demonstrated overexpression of EGFR (epidermal growth factor receptor) and VEGF (vascular endothelial growth factor receptor) in 23% and 57% of tumors, respectively, suggesting that drugs that target these receptors may play a role in therapy of this disease.
A phase II study was published recently supporting the use of cetuximab, a monoclonal antibody targeting EGFR, in combination with gemcitabine and oxaliplatin in first-line unresectable biliary tract cancer, with objective responses seen in 63% of patients.17
Bevacizumab, a monoclonal antibody that binds to the VEGF ligand, also demonstrated antitumor activity when used with the combination of gemcitabine and oxaliplatin in advanced biliary tract cancer.18
Finally, single-agent treatment with erlotinib, a tyrosine kinase inhibitor targeting EGFR, elicited partial responses in advanced biliary cancer.19
While only 3 patients in our review received any targeted therapy (2 erlotinib, 1 bevacizumab), this area remains an expanding field of research that we hope will lead to new treatment strategies in the future.
Now that phase III data exist to support a preferred regimen in advanced biliary tract tumors from the ABC-02 trial, a logical next step is to begin analyzing this heterogeneous group of tumors by subtypes to determine if these regimens work as effectively in each type of disease. We were able to compile these data due to the availability of charts from a relatively large group of patients with unresectable intrahepatic and hilar cholangiocarcinoma. In this retrospective analysis, both gemcitabine/cisplatin and capecitabine/oxaliplatin were effective regimens in maintaining disease control in this population. Further research is needed, preferably with multicenter collaboration to obtain larger homogenous populations, to determine which characteristics are present in patients with prolonged response and survival in advanced cholangiocarcinoma.