Definitive Liver Radiotherapy for Intrahepatic Cholangiocarcinoma with Extrahepatic Metastases

Abstract

Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods: We reviewed ICC patients found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose (BED10) was 98 Gy (interquartile range [IQR] 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazards modeling. Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; P=0.001). On multivariable propensity-score matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; P=0.005) and receipt of L-RT (HR 0.40; P=0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; P<0.001). Discussion/Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS vs. those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.

Proton Beam Therapy for Intrahepatic Cholangiocarcinoma: A Multicenter Prospective Registry Study in Japan

“…The MST in our registry is 21.7 months, which seems to be a good result compared to chemotherapy alone, but these data do not include cases with active distant metastases and the conditions were good even among unresectable ICC cases. De et al [43] have recently described the advantages of radiotherapy for ICC with metastases. In a comparison of chemotherapy alone with radiotherapy, 82% of deaths with chemotherapy alone were found to be caused by liver recurrence, but after radiotherapy this rate dropped to 47%, with distant metastasis becoming the leading cause of death [43].…”

“…De et al [43] have recently described the advantages of radiotherapy for ICC with metastases. In a comparison of chemotherapy alone with radiotherapy, 82% of deaths with chemotherapy alone were found to be caused by liver recurrence, but after radiotherapy this rate dropped to 47%, with distant metastasis becoming the leading cause of death [43]. It was concluded that radiotherapy is associated with a lower rate of death caused by liver recurrence and with longer survival [43].…”

What Role Does Radiotherapy Play in the Molecular Era for Intrahepatic Cholangiocarcinoma?

“…Indeed, among patients with M1 iCCA, similar to those with locally advanced unresectable disease, a majority of patients die of complications of tumor-related liver failure. For M1 iCCA patients, delivering ablative-dose radiotherapy to achieve LC of the dominant liver disease was found to be associated with prolonged OS compared with a parallel cohort of patients treated with chemotherapy alone as well as with a matched cohort from the National Cancer Database 55 . Notably, patients with M1 iCCA who received radiotherapy in this series were less likely to die of tumor-related liver failure than those who received systemic therapy alone, but those in the radiotherapy group were more likely to die of extrahepatic disease progression eventually.…”

“…A series of studies have demonstrated that in the era of gemcitabine/cisplatin, hepatic vascular compromise and biliary obstruction constitute the cause of death in the vast majority of patients with iCCA 53–55 . For example, in a retrospective study of 362 patients with unresectable iCCA, local tumor progression caused liver failure in 89% of patients 56 .…”

“…Even in the midst of the transition in standard-of-care practice regarding systemic therapy (as we enter the chemoimmunotherapy), the results of retrospective and prospective radiotherapy studies have influenced clinical practice in the United States, as the delivery of escalated doses of radiotherapy has steadily increased in utilization and continues to associate with prolonged OS based on real-world data 61 . Furthermore, the indication for radiotherapy may extend beyond locally advanced iCCA, as patients with extrahepatic metastases from iCCA (M1 disease) also seem to significantly benefit from ablative radiotherapy of the primary liver tumor on retrospective analysis 55 . Indeed, among patients with M1 iCCA, similar to those with locally advanced unresectable disease, a majority of patients die of complications of tumor-related liver failure.…”