At the 2025 Annual Cholangiocarcinoma Foundation Conference, a working group that included co-chairs Julien Edeline and Eugene Koay, as well as Bruno Sangro, Boris Guiu, Laura Dawson, Maria Hawkins, Mike Lidsky, Jennifer Wo, Lauen Henke, and Jackie Fowler, presented evidence for different locoregional treatments. These included ablation techniques, selective internal radiation therapy (SIRT), intra-arterial treatment including hepatic arterial infusion (HAI) and external beam radiation, and histotripsy.
Ablation therapy is frequently used in specific populations, generally for those who have contraindications to surgery, tumors sufficiently small for ablation, recurrence following surgery, and cirrhosis preventing surgery. A systematic review of ablation included 15 cohorts and 645 patients total demonstrated that 93% of patients had a complete ablation of their tumor with a promising median overall survival (OS) of 30 months. Other types of therapeutic interventions include radiofrequency ablation and photodynamic therapy.
With regard to intrahepatic cholangiocarcinoma (iCCA), radiation is used in selective patients. The standard of care for unresectable iCCA is systemic therapy. Escalated radiation is associated with high rates of local control in hepatocellular carcinoma (HCC) and iCCA. The role of extrahepatic cholangiocarcinoma (eCCA) depends on the stage of disease. Studies demonstrate encouraging rates of local control and OS of postsurgical chemoradiation in some patients, but the role of eCCA in unresectable disease remains undefined. There are opportunities for radiation therapy in cholangiocarcinoma. First, there are no randomized controlled trials for radiation in iCCA that have been completed. Second, evidence has been encouraging but is limited to single-arm prospective phase 2 trials, single-institution studies, or retrospective reviews, and large databases with limited clinical data. Third, there is heterogeneity in the studies. Patient selection is key, and biomarkers are needed. A retrospective study that first suggested external beam radiation had a role in the treatment of iCCA was conducted by MD Anderson Cancer Center. This study had a total of 79 patients with a median tumor size of 7.9 cm. The median follow-up was 33 months, and the median OS was 30 months. The 3-year OS rate was 44%. The single most prognostic factor was the radiation dose. Long-term survival with radiation is possible in unresected iCCA, and high-dose radiation with ablative intent may offer benefits. Biomarker evaluations and prospective trials are ongoing.
SIRT, also known as yttrium-90 radioembolization, is a radiation technique delivered through vascular access. Previously, the dose delivered did not consider the repartition of the dose within the treated liver. The tumor, healthy liver, and nontreated liver cells need to be differentiated. The MISPHEC prospective trial evaluated SIRT in 41 patients with iCCA. These patients were treated with concomitant SIRT and gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle for 8 cycles. The overall response rate was 39% and the median OS was 22 months. After a median follow-up of 36 months (95% confidence interval [CI], 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months). Challenges associated with performing randomized controlled trials for SIRT and other locoregional therapies include a limited patient population, expertise of different centers, competition with systemic therapy trials, difficulty raising industry’s interest in large trials, and the necessity to take into account heterogeneity of the patient population.
HAI is a locoregional treatment that involves physiological and pharmacologic isolation of the liver. It is known that liver tumors primarily derive their blood from the artery of the liver. The drug floxuridine (FUDR) is delivered directly in the artery to the liver. FUDR has a short half-life and is almost completely cleared by the liver. Optimal patients for HAI include those aged <80 years, ECOG of 0 or 1, having no cirrhosis or portal hypertension, having no active hepatitis, having suitable hepatic arterial anatomy, having no prior rare disease or radiation therapy, and the disease must be confined to the liver. Multiple phase 2 nonrandomized clinical trials (NCT01862315, NCT00866164) have used HAI for unresectable iCCA. In one of those trials, the PUMP II trial, 50 patients with liver-confined unresectable iCCA received HAI/FUDR for 6 cycles plus gemcitabine/cisplatin for 8 cycles. The primary outcome was 1-year OS. Thirty-four percent of patients had regional nodes, and 66% of patients had multifocal disease. At a median follow-up of 29 months, the median OS was 22 months. The 1-year OS rate was 80%, and the 3-year OS rate was 33%.
One of the more recent technological advancements is histotripsy, which uses highly focused, high-energy ultrasound waves to destroy cancerous tissue. The #HOPE4LIVER single-arm pivotal trials (NCT04572633, NCT04573881) for histotripsy of primary and metastatic liver tumors led to the FDA approval of this device. This study included a total of 44 patients from the United States (n=21) and the European Union and England (n=23) with an average age of 64 years. Eighteen patients had HCC, and 26 patients had non-HCC liver metastasis. The co-primary endpoints were technical success, defined as treatment volume larger than tumor volume and included tumor, and safety within 30 days. Technical success was achieved in 42 of 44 tumors, and procedure-related major complications occurred in 3 of 44 patients.
For iCCA, HAI, SIRT, and external beam radiation currently have the most evidence to support their use as locoregional therapies, with median survival times ranging from 20 to 24 months. Surgical resection is technically possible after these therapies. For eCCA, there are limited data, but external beam radiation is often incorporated in various settings. Additionally, there are no randomized controlled trials comparing locoregional therapies or validated biomarkers to select patients for locoregional therapies.
Edeline J, Koay E. WG7-Locoregional Therapies. Presented at: 2025 Annual Cholangiocarcinoma Foundation Conference. April 9-11, 2025; Salt Lake City, UT.
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