Systemic therapy for cholangiocarcinoma

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Cholangiocarcinoma (CCA) is an increasingly common biliary malignancy and accounting for 3% of all gastrointestinal tumors. In the United States, the incidence is 1 to 2 cases per 100,000 population and is uncommon compared with other cancer types. While the incidence of intrahepatic CCAs has been rising in industrialized countries, the incidence of extrahepatic CCA is declining worldwide.¹ CCA continues to have a high mortality, with a 5‐year survival rate of 10%.2 In the Western world, the most commonly associated risk factor for CCA is primary sclerosing cholangitis, with an annual risk of 0.5%‐1.5%. In addition, hepatitis B and C virus infection and cirrhosis have been proposed as risk factors for the development of intrahepatic CCA.2 CCAs can be divided into three distinct subtypes based on their anatomical site of origin: intrahepatic CCA, perihilar CCA, and distal (extrahepatic) CCA.3 Intrahepatic CCA is thought to develop from the biliary epithelial cell or hepatic progenitor cells, whereas perihilar and distal CCA are thought to arise from the peribiliary gland and biliary epithelium, respectively. While the pathogenesis of CCA has not been elucidated completely, inflammatory pathways are thought to be play an important pathological role, including elevated levels of interleukin‐6 and other cytokines, which over time can lead to oncogenesis.3 With these factors in mind, the successful development of systemic therapy for CCA has been limited.

Cytotoxics

Select patients with localized CCA can undergo surgical resection with curative intent. Despite the lack of randomized clinical trials in the adjuvant setting, a recent meta‐analysis of clinical trials supports the use of fluorouracil‐based chemoradiotherapy in patients with positive margins post‐resection or in whom lymph node–positive disease is identified.4 The lack of our understanding of the molecular diversity and drivers of cholangiocarcinoma has made cytotoxic chemotherapy the mainstay of treatment to date for patients with advanced disease. Several chemotherapy agents have been evaluated as single agents (Table 1) or in various combinations (Table 2). These have generally been small, single‐arm phase 2 studies that demonstrated modest response rates but no clear improvement in overall survival. These have included drugs such as 5‐fluorouracil, cisplatin, gemcitabine, and oxaliplatin. None of these studies established a definitive role for chemotherapy in this group of patients. Nevertheless, patients with good performance status and preserved renal and hepatic function should be offered systemic therapy. Patients that are bedbound with significant comorbidities and organ dysfunction are not appropriate candidates for systemic therapy.

Table 1.

Selected Phase 2 Clinical Trials of Single‐Agent Chemotherapy in CCA

Agent	n	Overall Response Rate	Progression‐Free Survival (months)	Overall Survival (months)	Reference
5‐FU/folinic acid	28	32%	NR	6	Choi et al. 15
Gemcitabine	23	30%	NR	NR	Kubicka et al. 16
Gemcitabine	23	26.1%	8.1	13.1	Park et al. 17
Docetaxel	24	20%	6.0	8.0	Papakostas et al. 18
Irinotecan	25	8%	NR	10	Sanz‐Altamira et al. 14

Abbreviation: NR, not reported.

Table 2.

Selected Phase 2 Clinical Trials of Combination Chemotherapy in CCA

Regimen	n	Overall Response Rate	Progression‐Free Survival (months)	Overall Survival (months)	Reference
Gemcitabine‐based
Gemcitabine + capecitabine	23	34%	9.0	19	Knox et al. 19
Gemcitabine + oxaliplatin	33	36%	5.7	15.4	Andre et al. 20
Gemcitabine + irinotecan	39	20.5%	4.3	7.6	Chung et al. 21
Oxaliplatin‐based
Oxaliplatin + irinotecan	28	17.9%	2.7	9.2	Karachaliou et al. 22
Oxaliplatin + capecitabine	56	27%			Nehls et al. 23
Distal CCA			6.5a	12.8
Intrahepatic CCA			2.2a	5.2

^aMedian time to progression.

Only in the past few years has there been a large randomized phase 3 study that has proven a survival benefit with chemotherapy in advanced disease.5 The ABC trial randomized 410 patients with locally advanced or metastatic bile duct (n = 242), gallbladder (n = 148), or ampullary (n = 20) cancers to six cycles of cisplatin (25 mg/m²) and gemcitabine (1000 mg/mg²) on days 1 and 8, every 21 days, or gemcitabine alone (1000 mg/m² on days 1, 8, and 15 and every 28 days).5 The trial demonstrated a statistically significant improvement in median overall survival with combination therapy (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80; P < 0.001) and improvement in progression‐free survival (8 versus 5 months; P < 0.001). Common adverse events (>10% of patients) included fatigue, and an increased risk of any infection, which occurred in similar rates in both groups; however, there was a nonsignificant increase in neutropenia and a significant increase in liver dysfunction for the cisplatin and gemcitabine combination group.

Molecular Targeted Therapy

The historically poor results with cytotoxics have highlighted the need for a new approach to the treatment of advanced disease. However, early results with novel agents have not been convincing. At this time, no molecular targets have been validated for the treatment of CCA. Laboratory studies suggest that distinct molecular subgroups of the disease do exist and that various receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 may be relevant targets for therapy.6 Clinical trials performed to date with targeted agents have mostly focused on targeting the EGFR family, angiogenesis, and recently mitogen‐activated protein/ERK kinase (MEK). These studies are summarized in Table 3. None of them have demonstrated robust efficacy, likely because of the lack of a predictive marker for response being incorporated into these studies.

Table 3.

Selected Clinical Trials with Molecular Targeted Agents in CCA

Agent	Line	Phase	n	Overall Response Rate	Progression‐Free Survival (months)	Overall Survival (months)	Reference
EGFR
GEMOX +/− erlotinib	1st	3	268	16% versus 30%	4.2 versus 5.8	9.5 versus 9.5	Lee et al. 8
GEMOX/cetuximab	1st	2	30	63%	8.8	15.2	Gruenberger et al. 9
GEMOX +/− cetuximab	1st	2	150	29% versus 23%	5.3 versus 6	12.4 versus 11	Malka et al. 10
Erlotinib	2nd	2	42	8%	2.6	7.5	Philip et al. 7
HER‐2
Lapatinib	2nd	2	17	0%	1.8	5.2	Ramanathan et al. 11
MEK
Selumitinib	2nd	2	56	12%	3.7	9.8	Bekaii‐Saab et al. 12
MEK 162	1st/2nd	1	28	8%	NR	NR	Finn et al. 13
VEGF
GEMOX + bevacizumab	1st	2	35	41%	7.6	14.2	Zhu et al. 24

Abbreviations: EGFR, epidermal growth factor receptor; HER‐2, human epidermal growth factor receptor 2; MEK, mitogen‐activated protein/ERK kinase; NR, not reported; VEGF, vascular endothelial growth factor.

In one study of 42 patients with advanced biliary cancers, 57% of whom had received prior chemotherapy, the EGFR kinase inhibitor erlotinib was given as a single agent. There were three partial responses and seven additional patients were progression‐free at 6 months.7 A randomized trial of gemcitabine and oxaliplatin (GEMOX) with or without erlotinib demonstrated an increased response rate (30% versus 16%; P = 0.004) in the erlotinib group, but progression‐free survival was not significantly improved (median, 5.8 months; 95% CI, 4.6%‐7.0% versus 4.2 months [CI, 2.7%‐5.7%]; P = 0.087).8 A phase 2 trial of GEMOX, and the EGFR monoclonal antibody cetuximab in 30 patients with previously untreated advance biliary tract cancer showed a 63% objective response rate with three complete responders⁹; however, a larger randomized trial (BINGO trial, n = 150) of GEMOX with or without cetuximab in a first‐line setting failed to demonstrate a statistically significant benefit in progression‐free survival or overall survival with addition of the antibody.10 In addition, a small molecule approach to dual targeting of both EGFR and human epidermal growth factor receptor 2 failed to demonstrate any significant activity.11 Efficacy benefit using lapatinib in targeting vascular endothelial growth factor was suggested in a phase 2 study of GEMOX and bevacizumab. In the 35 evaluable patients, in whom all but three had been previously untreated, the median progression‐free survival was 7.6 months (95% CI, 5.9–12.4) and the median overall survival was 14.2 months (CI, 6.8–22.0) (24). More recently, two studies have explored a role for targeting the RAS/RAF/MEK/ERK pathway, which is a common driver of proliferation in cancer. A single‐arm phase 2 study of the MEK inhibitor selumetinib in 56 patients in a second‐line setting resulted in a response rate of 12%, with 68% of patients achieving stable disease. The median progression‐free survival was 3.7 months and the overall survival was 9.8 months.12 The most recent data presented with a newer MEK inhibitor, MEK 162, evaluated single‐agent activity in 28 patients in both a front‐line and second‐line setting in a phase I expansion study.13 The compound was well‐tolerated at 60 mg twice daily and demonstrated some clinical activity, with one complete response and one partial response and 46% of patients having stable disease as the best response. There was no correlation seen with mutations in ras or raf and response.

Second‐Line Therapy and Beyond

One area of uncertainty is the appropriate management of patients who progress on first‐line systemic therapy. The most appropriate option given the lack of data would be participation in a clinical trial. A small phase 2 trial of irinotecan did include patients who had been treated with one line of systemic therapy, suggesting that the single agent irinotecan may exhibit activity in a second‐line setting.14 The erlotinib trial7 and trials of MEK inhibitors12, 13 also included patients who were treated previously, suggesting that these agents may exhibit activity in a second‐line setting. Currently, this is an area of great unmet need.

Conclusion

Only recently has a role for systemic therapy with gemcitabine and cisplatin been proven in advanced disease. Results from studies evaluating its role in early stage CCA are awaited. Currently, in the absence of appropriate clinical trials, the combination of gemcitabine and cisplatin is the preferred first‐line regimen for advanced disease.

More effective treatments and proven options constitute significant unmet needs for patients who fail first line therapy. Molecular targeted agents have had a significant impact in various tumor types, but their development to date in cholangiocarcinoma has been largely empirical. Until predictive markers of response are incorporated into prospective trials, it is unlikely that significant activity will be seen. Although there is no regimen proven to extend survival in a second‐line setting, outside of a clinical trial, it is not unreasonable to offer patients with preserved performance status and organ function systemic chemotherapy. Options include the singe agents capecitabine, 5‐fluorouracil, irinotecan, docetaxel, or the combination of oxaliplatin and capecitabine. An appreciation for the molecular heterogeneity of the clinical disease is lacking, and an effort to bridge the gap between the laboratory and the clinic is needed. Furthermore, randomized phase 2 studies will be required to truly evaluate early efficacy signals for the most promising agents to bring forward to phase 3. Still, at this time, patients should be encouraged to participate in clinical trials whenever possible.

Abbreviations

CCA

cholangiocarcinoma

EGFR

epidermal growth factor receptor.