Objectives: To determine the efficacy and safety of 2 doses of gadobutrol 1.0 M (0.1 and 0.2 mmol/kg body weight [BW]), compared with gadoteridol 0.5 M (0.2 mmol/kg BW), in contrast-enhanced magnetic resonance imaging (CE-MRI) of brain metastases in patients with known or suspected brain metastases from systemic malignancies. The study also compared the usefulness of gadobutrol in treatment planning for stereotactic radiosurgery (SRS).
Materials and methods: This was a Phase II/III, multicenter, single-blind, randomized, controlled, crossover, intraindividual comparison study. Each patient underwent one MRI study examination with gadobutrol and the other with gadoteridol, each at a dose of 0.1 mmol/kg BW, administered twice, for a total dose of 0.2 mmol/kg BW. Image acquisition was carried out after the first and second doses of gadobutrol, but only after the second dose of gadoteridol. Contrast agents were assigned in a randomized order and their administration separated by an interval of 1 to 14 days. Images were evaluated through blinded readings by 3 independent experienced radiologists. Treatment planning for SRS was assessed in a blinded manner, as a consensus between a diagnostic neuroradiologist and a radiation oncologist, in addition to the clinical investigator's assessment. The safety and tolerability of gadobutrol and gadoteridol were evaluated in all patients who received the study drugs. The primary efficacy variable was the number of lesions detected in CE-MRI images; the secondary efficacy variables were the degree of contrast enhancement and border delineation of lesions, and experts' confidence in treatment planning for SRS.
Results: A total of 175 patients were enrolled and randomized, with 164 (93.7%) included in the safety analysis set, and 151 (86.2%) evaluable in the efficacy analysis. The mean number of detected lesions per patient using the average of the 3 blinded readers was 6.28, 6.92, and 6.87 for gadobutrol 0.1 and 0.2 mmol/kg BW, and gadoteridol 0.2 mmol/kg BW, respectively. Noninferiority of gadobutrol (both doses) to gadoteridol 0.2 mmol/kg BW was demonstrated. The degree of contrast enhancement and the border delineation of each lesion were categorized as "good" or "excellent" for most lesions for both agents. Almost all enhanced images were rated as "confident" in treatment planning for SRS. Sixty-five (43%) and 62 (41%) patients in the gadobutrol 0.1 and 0.2 mmol/kg BW groups, respectively, were selected as eligible for SRS treatment. The percentage of images assessed as "gadobutrol was better than gadoteridol" was higher than that assessed as "gadoteridol was better than gadobutrol" for both doses of gadobutrol. Eight adverse events were reported as being related to the study drug in 7 patients (4.3%) in each group.
Conclusion: In this study, a single dose of gadobutrol was shown to be noninferior to a double dose of gadoteridol at detecting brain metastases, and could be effectively used for treatment planning in patients eligible for SRS. A dose of gadobutrol 0.1 mmol/kg BW is recommended as the clinical dose for the detection of brain metastases.
Trial registration: ClinicalTrials.gov NCT00522951.