Stereotactic Body Radiation Therapy After Chemotherapy for Unresectable Perihilar Cholangiocarcinoma

Rationale:

For patients with perihilar cholangiocarcinoma, surgery is the only treatment modality that can result in cure. Unfortunately, in the majority of these patients the tumors are found to be unresectable at presentation due to local invasive tumor growth or the presence of distal metastases. For patients with unresectable cholangiocarcinoma, palliative chemotherapy is the standard treatment, yielding an estimated median overall survival of 12-15.2 months.

There is no evidence from randomized trials that support the routine use of stereotactic body radiation therapy (SBRT) for cholangiocarcinoma. The STRONG phase I feasibility study showed favorable outcomes regarding safety, and the therapy was generally well tolerated. Based upon these observations, a phase II multi-center study with SBRT after chemotherapy in patients with unresectable perihilar cholangiocarcinoma is proposed, in order to further research the efficacy of adding SBRT to standard chemotherapy.

In addition, an explorative translational research component is part of the study, in which peripheral immunodynamics, specifically myeloid nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) signaling and interferon-stimulated genes (ISG) responses within the myeloid cells, may help to predict survival after chemotherapy and may also help to predict the value of additional treatment with radiotherapy.

Objective:

The objective of this study is to evaluate the efficacy of SBRT as additional treatment after standard chemotherapy regarding tumor local control, toxicity, progression-free survival (PFS), overall survival and quality of life. In addition, to explore the value of immunodynamics in peripheral blood for predicting PFS in patients undergoing chemotherapy.

Study design:

Single-arm, multicenter phase II study.

Study population:

The initial translational part of the study will be performed in patients diagnosed with unresectable perihilar cholangiocarcinoma, 18 years of age or older, T1-4 N0-2 M0 (AJCC staging 8th edition), eligible for gemcitabine-based chemotherapy. Exclusion criteria are tumor extension into either stomach, colon, duodenum, pancreas or abdominal wall. After completion of chemotherapy and no local or distant progression during or after chemotherapy, the patients will proceed to SBRT if they are still eligible based on the inclusion and exclusion criteria. It may occur that patients do not give consent for the translational part of the study, but they may wish to participate in the SBRT part of the trial and vice versa. Sample size will be 30 patients.

Intervention:

SBRT will be delivered in 15 fractions of 4 to 4.5Gy after 8 cycles of chemotherapy. In case of toxicity causing premature termination of systemic treatment, the patient can still proceed to SBRT.

Main study parameters/endpoints:

The primary endpoint of this study is local tumour control, defined as time from inclusion to local radiological progression. Definition of progression is based on response evaluation criteria in solid tumours (RECIST) 1.1.

Secondary endpoints:

* Toxicity according to the Common Toxicity Criteria for Adverse Events (CTCAE) V.5.0 grading system. * Biliary stent-related events (SRE). * Progression-free survival defined as time from inclusion until radiological progression. Definition of progression is based on RECIST 1.1. * Overall survival defined as time from inclusion until death from any cause. * Quality of life (QoL), assessed by means of the EuroQol (EQ)-5D-5L (measure of health outcome in general population), and the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (QoL specific for patients with cancer) with the supplementary module EORTC QLQ-BIL21 (specific for CCA and gallbladder cancer).

• Progression-free survival (PFS) [Срок оценки: 42 months (maximum follow-up time)]
• Overall survival (OS) [Срок оценки: 42 months (maximum follow-up time)]
• Adverse events [Срок оценки: 42 months (maximum follow-up time)]
• Biliary stent-related events (SRE) [Срок оценки: 42 months (maximum follow-up time)]
• Quality of life (QoL) - EQ-5D-5L [Срок оценки: 36 months]
• Quality of life (QoL) - QLQ-C30 [Срок оценки: 36 months]
• Quality of life (QoL) - QLQ-BIL21 [Срок оценки: 36 months]