Y-90 radioembolization is a promising locoregional therapy for a devastating disease with few available treatment options. Ongoing and future clinical trials will help to determine if Y-90 radioembolization can safely be integrated with systemic chemotherapy, writes William Rilling, Milwaukee, USA.
Often overshadowed by hepatocellular carcinoma, cholangiocarcinoma is frequently referred to as “the other liver cancer”. This is a rare but devastating malignancy with poor five-year overall survival rates of <5%. Surgical resection is the only standard curative treatment. However, only 20–30% of patients present with resectable disease and intrahepatic recurrence is common even after an R-0 surgical resection. Transplant is performed in very highly selected patients who undergo a rigorous pretransplant protocol and the long-term results of liver transplant for this disease are still somewhat uncertain.
The overall management of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma differ significantly. Extrahepatic cholangiocarcinoma is managed surgically when possible, occasionally aided by transhepatic biliary stents for hilar cholangiocarcinoma. Adjuvant chemoradiation is sometimes employed post-resection. Y-90 radioembolization does not play a role, at this time, in the treatment of extrahepatic cholangiocarcinoma, but there is growing evidence of its benefit in the treatment of intrahepatic cholangiocarcinoma.
Despite its aggressive nature, chemotherapy for cholangiocarcinoma has had limited success. Current standard of care chemotherapy includes gemcitabine and cisplatin with reported median survival of 12 months and progression free survival of eight months in a phase III trial published in the New England Journal of Medicine in 2010. Both National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines do not endorse any specific second line chemotherapy regimen.
Multiple retrospective single centre series have been published reporting the safety and efficacy for Y-90 radioembolization in unresectable intrahepatic cholangiocarcinoma. Median overall survival ranging from nine to 22 months were reported in some of the initial single-centre reports. The majority of these patients were treated in a salvage situation following progression on systemic chemotherapy. Overall response rates to Y-90 radioembolization show progressive disease in the liver in only 15–25% of patients with disease control obtained (combination of partial response and stable disease) in 75–80% of patients. Another clear advantage of Y-90 radioembolization is the excellent tolerance of the therapy and low toxicity. The incidence of high-grade adverse events in all published series is rare. Most patients require only one or two treatment sessions, preserving quality of life in this patient population with limited survival.
A recent pooled analysis of Y-90 radioembolization for intrahepatic cholangiocarcinoma was published in the European Journal of Surgical Oncology in 2015. The analysis included 298 patients in 12 studies. Overall median survival was 15.5 months. Tumour response rates were partial response in 28% and stable disease in 54% at three months post treatment.
Other liver-directed therapies, primarily chemoembolization, have also been shown to be effective in intrahepatic cholangiocarcinoma. In a recent multicentre review, 198 patients with unresectable intrahepatic cholangiocarcinoma reviewed were treated at five institutions over 20 years in the USA. The majority of patients in this review (128) have been treated with conventional chemoembolization and with 46 patients treated with Y-90 radioembolization. There was no significant difference in the overall survival between these two therapies in this retrospective review.
These data have prompted NCCN to include locoregional therapy as one of the treatment options for unresectable and recurrent intrahepatic cholangiocarcinoma. The ESMO guidelines also endorse locoregional therapy including Y-90 radioembolization for second line treatment of locally advanced or metastatic intrahepatic cholangiocarcinoma.
Based on the reported success of these early studies, a prospective phase II trial has been initiated to study the safety and efficacy of combining Y-90 radioembolization with gemcitabine and cisplatin for unresectable intrahepatic cholangiocarcinoma. The study will be using Y-90 resin microspheres and is currently enrolling and additional phase III studies are planned.
In summary, Y-90 radioembolization is a promising locoregional therapy for a devastating disease with few available treatment options. Ongoing and future clinical trials will help to determine if Y-90 radioembolization can safely be integrated with systemic chemotherapy. Future research is needed to further define the role of different locoregional therapies in this disease, which is increasing in incidence worldwide.
William Rilling is professor of Radiology and Surgery, Vascular and Interventional Radiology and vice chair, Clinical Operations, Department of Radiology, Medical College of Wisconsin, Milwaukee, USA. He is a consultant for BTG and receives research support from Sirtex for clinical trials.