Stereotactic Body Radiation Therapy Following Chemotherapy for Unresectable Perihilar Cholangiocarcinoma: The STRONG Trial, a Phase I Feasibility Study

Purpose/objective(s) Patients with perihilar cholangiocarcinoma (pCCA) can only be cured by surgery. The standard of care for those with inoperable tumors is palliative chemotherapy. In an attempt to control the disease locally without adding severe toxicity in patients with unresectable pCCA, we investigated the safety and feasibility of adding stereotactic body radiation therapy (SBRT) after chemotherapy. Materials/methods Patients were eligible with a diagnosis of unresectable pCCA, stage T1-T4N0-N1M0 (AJCC staging 7th edition), ECOG performance status of 0-1, and having finished 6-8 cycles chemotherapy treatment (cisplatin and gemcitabine). SBRT was planned in 15 fractions of 3.0-4.5Gy, aiming for a biologically effective dose > 80.5Gy, while not exceeding organs at risk (OAR) constraints. The primary endpoints were feasibility, defined as completing SBRT as planned, and toxicity evaluated within 3 months of treatment. A conventional '3+3'-design was used, corresponding to a sample size of 6 patients. Toxicity was scored with the CTCAE v4.03 grading system. Dose-limiting toxicity (DLT) was defined as grade ≥4 hepatobiliary or grade ≥3 gastrointestinal toxicity. Secondary endpoints, measured from start of radiotherapy, were local control, progression-free survival (RECIST 1.1), overall survival, and quality of life (QoL). QoL was measured using the QLQ-C30, EQ-5D-5L, and QLQ-BIL21 questionnaires. Results Six patients were enrolled between 1 November 2017 and 30 March 2020. All patients completed 6-8 cycles of chemotherapy. They were staged T4N0-1M0, each with unresectable disease due to vascular involvement. SBRT was completed as planned. A dose of 60Gy (15×4.0Gy) was prescribed at the 80% isodose. Due to OAR constraints, especially duodenum, the median PTV coverage was limited to 82.4% (75.7%-89.6%). No SBRT related DLT was observed. The most common grade ≥3 toxicity was cholangitis (n = 5), which could be resolved by improving biliary drainage. The 12-month local control rate was 80%. Metastases emerged in the form of peritoneal metastases/ascites (n = 3) and/or liver metastases (n = 1). Three of the 4 patients who developed distant metastases had lymph-node-positive disease at baseline. After a median follow up of 14 months, 4 of 6 patients were still alive. We observed no substantial changes in QoL. Median QLQ-C30 'global health status' scores were 75.0 at baseline, 3 months and 12 months. Conclusion Fractionated SBRT following standard chemotherapy was a feasible and safe local therapy option for unresectable pCCA, albeit with the use of hard constraints for OAR. Cholangitis was often observed, but was reversible and QoL was maintained. Based upon the observed safety and the promising local control, additional evaluation of effectiveness in larger studies is warranted.