On-treatment Surveillance of Tumor Evolution and Response to Systemic Treatment in Bile Duct and Liver Cancer

The BILLIONSTARS study is a prospective, single arm observational study. Patients at Skåne University Hospital in Malmö/Lund and Central Hospital in Kristianstad diagnosed with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCC) who are to be recommended locoregional intervention by surgery, ablation or transarterial chemoembolization and/or antitumoral medical treatment will be included. A total enrolment of 150 patients is planned.

Before start of treatment, the patients will receive information about the study by a physician and give their written informed consent. Tumor tissue will be obtained from surgical specimens, predominantly from formalin-fixed paraffin embedded (FFPE) tissue, but in some cases, fresh tissue will be obtained at surgery for cryopreservation to enable future preclinical studies. All blood samples will be taken by a dedicated research nurse in conjunction with the treatment visits. Plasma, serum and buffy coat will be isolated from blood samples, following standard fractionation, to enable analyses of circulating tumor DNA (ctDNA), and other biomarkers. Participants will be asked to fill in quality of life questionnaires (EORTC QLQ-C30 and EORTC-QLQ-HCC18/BIL21) at study start, and after three and six months, respectively.

Treatment regimen will follow national guidelines and will not be affected by participation in the study. Radiological and clinical follow ups will be conducted according to clinical protocols or when deemed necessary by the clinician. Primary endpoint is OS, secondary endpoints are progression free survival and change in quality of life (EORTC QLQ-C30+EORTC-QLQ-HCC18/BIL21).

The study will also include research autopsies. Patients are informed and provide their consent for inclusion in this part of the study when they are in a late palliative phase.

Primary outcomes

• Overall survival [From date of inclusion until the date of death from any cause, assessed up to 60 months"]

Secondary outcomes

• Progression free survival [From date of inclusion until the date of first documented progression or death from any cause, whichever comes first, assessed up to 60 months.]
• Impact on quality of life [To be filled out at baseline, at three and at six months.]: Change in quality of life as measured by the form "European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cancer 30 (QLQ-C30). For questions 1-28 the minimum value is 28 and the maximum value is 112, where a higher value indicates worse symptom impact. For questions 29-30 the minimum value is 2 and the maximum value is 14 where a higher value indicates better health status and quality of life.
• Impact on quality of life HCC-specific [To be filled out at baseline, at three and at six months.]: Change in quality of life as measured by the form "European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18 (QLQ-HCC18). For the18 questions the minimum value is 18 and the maximum value is 72, where a higher value indicates worse symptom impact.
• Impact on quality of life BTC-specific [To be filled out at baseline, at three and at six months.]: Change in quality of life as measured by the form "European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Biliary Tract Cancer 18 (QLQ-BIL21). For the 21 questions the minimum value is 21 and the maximum value is 84, where a higher value indicates worse symptom impact.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* > 18 years of age
* Clinically diagnosed intrahepatic Cholangiocarcinoma (iCCC), perihilar Cholangiocarcinoma (pCCC), distal Cholangiocarcinoma (dCCC), gall bladder carcinoma (GBC) or mixed Hepatocellular carcinoma/Cholangiocarcinoma planned to undergo surgery
* Histologically or cytologically confirmed Cholangiocarcinoma (iCCC, pCCC, dCCC, GBC, mixed HCC/CCC) for patients planned to receive palliative systemic treatment or
* Clinically diagnosed Hepatocellular carcinoma (HCC) planned for surgery, ablation or transarterial chemo-embolization. For patients planned to receive systemic treatment histological or cytological confirmation is required except for patients with LI-RADS 5 lesions.

Exclusion Criteria:

* < 18 years of age
* Severe comorbidities
* Inability to comprehend study information

• Results publication: Falk P, Olsson Hau S, Jacobsen H, Eberhard J, Williamsson C, Jirstrom K. The bile duct and liver cancer: ON-treatment surveillance of tumor evolution and response to systemic treatment (BILLIONSTARS) study. BMC Cancer. 2025 Jun 11;25(1):1017. doi: 10.1186/s12885-025-14429-w. PMID 40500706

• Karin Jirström, PhD, MD, professor, Principal investigator, Region Skane