Study Protocol PROMETHEUS: Prospective Multicenter Study to Evaluate the Correlation Between Safety Margin and Local Recurrence After Thermal Ablation Using Image Co-registration in Patients with Hepatocellular Carcinoma

Timo T M Oosterveer*, Gonnie C M van Erp, Pim Hendriks, Alexander Broersen, Christiaan G Overduin, Carla S P van Rijswijk, Arian R van Erkel, Rutger W van der Meer, Maarten E Tushuizen, Adriaan Moelker, Martijn R Meijerink, Otto M van Delden, Koert P de Jong, Christiaan van der Leij, Maarten L J Smits, Thijs A J Urlings, Jeffrey P B M Braak, Elma Meershoek-Klein Kranenbarg, Bianca van Duijn-de Vreugd, Evelijn ZeijdnerJelle J Goeman, Jurgen J Fütterer, Minneke J Coenraad, Jouke Dijkstra, Mark C Burgmans

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


PURPOSE: The primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of < 10% in patients with hepatocellular carcinoma undergoing thermal ablation. Secondary objectives are to analyze the correlation between ablation margins and local recurrence and to assess efficacy.

MATERIALS AND METHODS: This study is a prospective, multicenter, non-experimental, non-comparative, open-label study. Patients > 18 years with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma (or B with a maximum of two lesions < 5 cm each) are eligible. Patients will undergo dual-phase contrast-enhanced computed tomography directly before and after ablation. Ablation margins will be quantitatively assessed using co-registration software, blinding assessors (i.e. two experienced radiologists) for outcome. Presence and location of recurrence are evaluated independently on follow-up scans by two other experienced radiologists, blinded for the quantitative margin analysis. A sample size of 189 tumors (~ 145 patients) is required to show with 80% power that the risk of local recurrence is confidently below 10%. A two-sided binomial z-test will be used to test the null hypothesis that the local recurrence rate is ≥ 10% for patients with a minimal ablation margin ≥ 2 mm. Logistic regression will be used to find the relationship between minimal ablation margins and local recurrence. Kaplan-Meier estimates are used to assess local and overall recurrence, disease-free and overall survival.

DISCUSSION: It is expected that this study will result in a clear understanding of the correlation between ablation margins and local recurrence. Using co-registration software in future patients undergoing ablation for hepatocellular carcinoma may improve intraprocedural evaluation of technical success. Trial registration The Netherlands Trial Register (NL9713), .

Original languageEnglish
Pages (from-to)606-612
Number of pages7
JournalCardiovascular and Interventional Radiology
Issue number5
Early online date1 Mar 2022
Publication statusPublished - May 2022


  • Co-registration
  • Hepatocellular carcinoma
  • Local recurrence
  • Minimal ablation margin
  • Thermal ablation

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