Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

BACKGROUND & AIMS: The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. METHODS: Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status <2 were screened. Radioembolization was administered using a sequential lobar approach. On day 3 after the last radioembolization procedure, sorafenib 200 mg twice daily was initiated escalating to 400 mg twice daily 1 week later; a matching sorafenib dose schedule was initiated in the control arm. RESULTS: Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. CONCLUSIONS: Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone.

High-dose Gd-DTPA vs. Bis-Gd-mesoporphyrin for monitoring laser-induced tissue necrosis.

PURPOSE: To compare Bis-Gd-mesoporphyrin (Bis-Gd-MP), a contrast agent with a reported high affinity to necrotic tissue, with high-dose gadopentate dimeglumin (Gd-DTPA) for defining laser-induced muscle and liver necrosis by contrast-enhanced (CE) MRI. MATERIALS AND METHODS: Laser-induced interstitial thermotherapy (LITT) was performed in the muscle and liver tissue of New Zealand White rabbits (1500 J and 2100 J; n=80 lesions). The animals were randomly assigned to a group that received 0.3 mmol/kg bw Gd-DTPA or a group that received 0.05 mmol/kg bw Bis-Gd-MP. Following contrast injection, dynamic MRI was performed on muscle lesions with a T1-weighted, two-dimensional, fast low-angle shot (FLASH) sequence. The liver and muscle lesions were then repeatedly imaged for six hours after contrast injection using a T1-weighted spin-echo (SE) sequence. Central and peripheral lesion enhancement was determined and correlated with gross pathology and microscopy findings. RESULTS: Both contrast agents allowed precise determination of lesion diameters with an average accuracy of 6.8%+/-1.3%. Rim enhancement during dynamic MRI was superior for Gd-DTPA (P<0.001) and revealed slightly higher lesion diameters compared to the results of follow-up MR studies. A persistent enhancement of necrotic liver and muscle tissue was observed for both contrast agents throughout the observation period, suggesting that simple diffusion-type processes may underlie the supposed affinity of Bis-Gd-MP for tissue necrosis. CONCLUSION: Bis-Gd-MP and Gd-DTPA are equally well suited for postinterventional lesion assessment in LITT.

Accuracy of non-enhanced MRI to monitor histological lesion size during laser-induced interstitial thermotherapy.

The purpose of this study was to assess the accuracy of non-enhanced MRI using a T1-weighted 2D turbo fast low-angle shot (FLASH) sequence during laser-induced interstitial thermotherapy (LITT) to determine histological lesion size of laser-induced hepatic lesions. The LITT was performed on pig liver samples at various power settings and durations. For MR monitoring during and after LITT a T1-weighted 2D turbo-FLASH sequence was applied. Lesions seen by MRI during and after LITT were correlated with histological lesion size. Histologically, a core zone of complete tissue ablation close to the tip of the applicator could be differentiated from an adjacent transitional zone showing incomplete necrosis. Magnetic resonance imaging right at the end of LITT (i.e., with maximum heating effects) grossly overestimated the core zone but accurately described the transitional zone. Magnetic resonance imaging after cooling of the tissue (therefore showing structural as opposed to thermal changes) exactly depicted the core zone of complete tissue ablation. Non-enhanced MRI using a T1-weighted 2D turbo FLASH sequence strongly overestimates the histological lesion size during LITT; however, structural changes of the tissue seen after cooling accurately define lesion size in LITT. For clinical purposes the lesion geometry seen during MR monitoring should therefore well extend the tumor margins.