Trial Design and Study Setting
The PROMETHEUS trial is a prospective, multicenter, non-experimental, non-comparative, open-label study. The sponsor of the study is the Leiden University Medical Center (LUMC). This study is a collaboration between Dutch academic centers and cancer organizations. The trial is funded by the Dutch Cancer Society and registered at https://www.trialregister.nl (ID: NL9713).
Patients over 18 years with Barcelona Clinic Liver Cancer stage 0-A HCC, or stage B with a maximum of two lesions < 5 cm each, are eligible. Full inclusion and exclusion criteria are provided in Table 1.
All patients are discussed in a multidisciplinary tumor board for eligibility and consented prior to inclusion. The ablation procedure and follow-up will be according to local standard of care. Interventions and important time points are shown in Fig. 1.
Both radiofrequency ablation (RFA) and microwave ablation (MWA) are allowed in the study. All patients will undergo dual-phase contrast-enhanced computed tomography (CECT), i.e. arterial and venous phase, directly before and after the ablation. Ablation and CECT will be performed under general anesthesia. The pre-ablation and post-ablation CECT will be performed during apnea to minimize breathing artifacts. Alternatively, high-frequency jet ventilation may be used.
At the end of the procedure, the interventional radiologist will determine whether complete tumor ablation with sufficient margins was achieved. All patients will be treated with the intent to obtain complete tumor ablation with a > 5 mm margin and it is left at the discretion of the treating interventional radiologist to determine whether technical success has been achieved. Assessment will be performed as per current practice, i.e. visual qualitative assessment in most centers. Peri-procedural care will be in accordance with the protocol of the local institution.
Patients will undergo physical examination, laboratory tests, contrast-enhanced magnetic resonance imaging of the liver and chest-CT every 3–4 months after ablation until liver transplantation, untreatable progression, or death. Follow-up scans will be reviewed independently by two experienced interventional radiologists, other than the radiologists assessing the quantitative MAM (see MAM analysis), to determine the presence and location of recurrence. These radiologists will be blinded for the analyses of the quantitative MAM. Disagreement between the two radiologists will be resolved by consensus reading.
All pre- and post-ablation CECT images will be transferred online to the LUMC using ALEA Clinical (FormsVision, The Netherlands). Two experienced interventional radiologists, blinded for outcome, will independently perform delineation of the tumor and ablation zone, on the pre-and post-ablation CECT respectively. The pre-and post-ablation CECT will be co-registered using post-processing software (deLIVERed, LUMC) to quantitatively assess the MAM (Fig. 2). Discordances of > 3 mm between both radiologists will be resolved by consensus reading, otherwise, the mean MAM will be calculated. The mean MAM will then be correlated with the presence and location of LR. The results of deLIVERed will be compared with SAFIR (Fraunhofer-Gesellschaft) software to determine whether results are reproducible using different co-registration software. All clinical data will be entered in Castor Electronic Data Capture and subsequently analyzed using appropriate software packages (SPSS or R).
The primary endpoint is the MAM that results in an LRR < 10% at 1-year follow-up.
LR at 1 year will be analyzed for different MAM categories: < 0 mm, 0–3 mm, 3–5 mm, and \(\ge\) 5 mm. Also, local and overall recurrence rates and disease-free survival (DFS) and overall survival (OS) at 1, 2, and 3 years will be analyzed. Finally, the relation between LR and DFS and OS will be investigated.
A sample size of 189 tumors would be sufficient to show with 80% power that the risk of LR is confidently below 10%, assuming a true risk of 4% for tumors ablated with a MAM ≥ 2 mm, based on a study by Kim et al. . Other retrospective studies into local recurrence provide similar numbers as provided by Kim et al. [5,6,7]. The calculation is based on the normal approximation of the binomial distribution (d = 0.10–0.04 = 0.06; s = sqrt(0.04 * 0.96) = 0.20; z = 1.96 + 0.84 (80% power); N = (s*z/d)2 = 84 tumors with ablation margin ≥ 2 mm; total number of tumors N = 84/0.445 = 189). Based on our own data, patients will have an average of 1.3 tumors per patient. Thus for 80% power, a sample size of 145 patients is indicated. Taking a potential drop-out rate of 10% into account, the needed sample size is 165 patients.
For the primary objective, a two-sided binomial z-test will be used to test (reject) the null hypothesis that the LRR is ≥ 10% for patients with a MAM ≥ 2 mm. Additionally, as a secondary analysis, a logistic regression model will be used to find the relationship between MAM and LR. Kaplan–Meier estimates will be used to assess local and overall recurrence, DFS, and OS. Survival data will be censored at the date of last follow-up if patients are still alive. The log-rank test will be used to compare recurrence for different MAM categories. Logistic regression analyses will be performed to determine possible independent predictors for local and overall recurrence, DFS, and OS. A p-value < 0.05 will be considered significant.