Contrast-enhanced magnetic resonance imaging (MRI) is an integral and indispensable part of modern imaging diagnostics. Gadolinium-based contrast agents (GBCAs) are the mainstay contrast-enhancing agents for MRI. Gadolinium-based contrast agents enhance different tissues differently, thereby improving the detection and characterization of pathologies anywhere in the body.

Gadobutrol (Gadovist 1.0; Bayer AG, Leverkusen, Germany) is a well-established macrocyclic, nonionic, extracellular, multipurpose, high-relaxivity GBCA.1 Importantly, gadobutrol features a higher relaxivity compared with the 2 other established macrocyclic GBCAs gadoteric acid (Dotarem; Guerbet, Villepinte, France) and gadoteridol (ProHance; Bracco, Milan, Italy) (4.6–5.3 L/mmol-s at 1.5 T, 3.5–5.0 L/mmol-s at 3 T, and 3.8–4.7 L/mmol-s at 7 T).2 Further, gadobutrol is available in a 1-molar concentration, that is, the double Gd concentration of the other GBCAs, which are all formulated in a 0.5-molar concentration.

The standard dose of gadobutrol is 0.1 mmol Gd/kg body weight (bw) (0.1 mL/kg bw). In Europe, the minimum dose (only for gadobutrol not for other GBCAs) for imaging of the central nervous system (CNS) is 0.075 mmol Gd/kg bw, and the maximum dose is 0.3 mmol/kg bw.3 A fixed volume is recommended for magnetic resonance angiography (MRA) based on bw and the number of fields of view (some country-specific labels vary).

Gadobutrol received the first approval for imaging the CNS in 1998 in Switzerland.1 Subsequently, approval in Europe for MRA, for liver and kidney imaging, and for use in children >2 years followed. In 2012, the “whole-body indication” and, in 2015, the approval for use in children <2 years were granted.

By December 2022, gadobutrol has been administered more than 100 million times worldwide. A total of 7856 patients were included in clinical development studies phase II–IV. More than 4000 manuscripts on gadobutrol have been published so far. Today, gadobutrol is marketed in 103 countries worldwide.

The purpose of this review is to provide a comprehensive literature-based overview on gadobutrol's efficacy in 9 approved indications and use in children. To this end, a systematic literature search on studies using gadobutrol was conducted in Embase (Excerpta Medica database), and the efficacy parameters “sensitivity” and “specificity” were extracted, as these parameters are well defined and describe the presence or absence of disease, independent of the organ system investigated. The safety aspects were also analyzed and will be covered in a separate review.

MATERIALS AND METHODS

The systematic literature review (SLR) was performed in Embase up until December 31, 2022, by a librarian with over 20 years of experience. The search string started with “gadobutrol” and “sensitivity/specificity” followed by the “indication.” Deeper analysis was performed manually on the full text. Only original data were used. Preclinical studies, models, reviews, and meta-analyses were excluded. Studies that used gadobutrol plus other GBCAs and did not differentiate between the agents were excluded. As several studies were identified in the SLR for each indication, always the 2 largest studies were described in more detail.

Results for blinded off-site reading were preferred when available. Always the lowest and highest values were picked for figures 2 (sensitivity) and 3 (specificity).

The indications in focus were as follows: CNS, MRA (lower extremities, kidneys, lungs), breast, heart, prostate, kidney, liver, musculoskeletal (MSK), whole body, and various indications in children (Fig. 1).

FIGURE 1: Literature search strategy (up to December 31, 2022). *One study included many body parts, not included here.4 This study represents the indication “whole body.” Children are a special population including many indications. As a result: 9 indications and use in children. One heart study was identified outside the search,5 resulting in a total of 65 studies.RESULTS AND ASSESSMENT

Sixty-five publications meeting the inclusion criteria were identified, covering 9 indications and use in children. Diagnostic efficacy results were reported for 7806 patients, including 271 children, from 369 centers worldwide. There were 10 phase III, 2 phase IV, and 53 investigator-initiated studies (IIRs), with 36 studies conducted prospectively and 54 evaluated by blinded read (Table 1). The overall sensitivity ranged from 53.4% to 100%, and specificity ranged from 64% to 100% (Table 2; Figs. 2 and 3).

TABLE 1 - Study Design Overview by Indication Indication No. Studies Phase III/IV/IIR No. Centers No. Patients Prospective/Retrospective Blinded/Nonblinded Reading† CNS 9 2/1/6 92 930 4/5 6/3 MRA 10 2/1/7 96 1150 8/2 10/0 Breast 10 2/0/8 77 2264 5/5 9/1 Heart 8 1/0/7 36 1312 8/0 8/0 Prostate 5 0/0/5 5 543 2/3 5/0 Kidney 2 1/0/1 2* 247 2/0 2/0 Liver 4 1/0/3 28 433 2/2 2/2 MSK 7 0/0/7 7 488 3/4 7/0 Whole body 1 1/0/0 17 168 1/0 1/0 Children‡ 9 0/0/9 9 271 1/9 4/0 Total 65 10/2/53 369 7806 36/29 54/6† *Tombach et al6 do not provide number of centers.

†Five articles did not mention blinding.

‡Children are a population that includes many different indications.

CNS, central nervous system; MRA, magnetic resonance angiography; MSK, musculoskeletal.

TABLE 2 - Efficacy Results of Gadobutrol in Different Indications (65 Studies, n = 7806 Patients Including 271 Children) Author (Year) Indication/Parameter* N Total† Study Design‡ SOR Sensitivity % Specificity % Accuracy % PPV % NPV % CNS (n = 930) Bernaerts et al,7 2022 Ménière disease/EH + PE 29 Retrospective, IIR, 1 center, blinded read Clinical function tests 91 98 Chung et al,8 2022 Facial neuritis/cranial nerve MRI 60 Retrospective, IIR, 1 center, unblinded read Clinical diagnosis 97.8 100 98.9 100 97.8 Gutierrez et al,9 2015 Clinical symptoms/malignancy 336 Prospective, phase III, 51 centers, blinded read Truth committee 66.7 97.5 87.7 Liu et al,10 2021 Brain lesion/malignancy 141 Prospective, phase IV, 20 centers, blinded read All clinical information 58.7 91.8 70.2 Morabito et al,11 2019 Differentiation: radiation necrosis vs tumor recurrence 28 Retrospective, IIR, 1 center, unblinded read Clinicoradiological criteria 88–89 75–97 Panyaping et al,12 2020 Differentiation: primary CNS lymphoma/HGG 41 Retrospective, IIR, 1 center, blinded read Histopathology 78.9 90.9 85.4 88.2 88.3(60) Seong et al,13 2020 Leptomeningeal metastases of lung adenocarcinoma 35 Retrospective, IIR, 1 center, blinding not mentioned Cerebrospinal fluid cytology 82.9 Tanaka et al,14 2016 Clinical symptoms/malignancy 223 Prospective, phase III, 15 centers, blinded reading Truth committee 74.6 98.7 91.4 Zakhari et al,15 2018 HGG/radiation necrosis 37 Prospective; IIR, 1 center, blinded reading Histopathology 75 88.9 85.7 80 MRA (n = 1150) Burbelko et al,16 2013 PAOD/pelvis, thigh, calf 152 Prospective, IIR, 1 center, blinded reading DSA 73–93 64–89 Fabrega-Foster et al,17 2018 Renal artery disease/stenosis 292 Prospective, phase III, 55 centers, blinded reading CTA 53.4 95.1 Hentsch et al,18 2003 PAOD/clinically significant stenosis, occlusion 203 Prospective, IIR/phase III, 10 centers, blinded reading DSA 71–76; 75–82 87–93; 94–98 Herborn et al,19 2004 PAOD/stenosis in lower extremity 51 Prospective, IIR, 1 center, blinded reading DSA 92.3–93.1 87.6–89.2 Kaya et al,20 2019 Pulmonary embolism/pulmonary artery 44 Prospective, IIR, 1 center, blinded reading CTA 100 90.9 97.7 97.1 100 Loewe et al,21 2015 PAOD/stenosis in lower extremity 79 Prospective, phase IV, 15 centers, blinded reading DSA 61.5–71 85.2–91.1 Mohrs et al,22 2004 Aortic aneurysm/renal/iliac artery stenosis 19 Prospective, IIR, 1 center, blinded reading DSA 96 99 96 99 Schaefer et al,23 2007 Carotid, common, and external iliac arteries stenosis >50% 179 Prospective, phase III, 10 centers, blinded reading DSA 76–96 86–94 87–93 44–91 84–98 Seeger et al,24 2008 Hemodynamically relevant stenoses, multiple vessels 80 Retrospective, IIR, 1 center, blinded reading DSA 94 94 Trelles et al,25 2013 Suspected stroke or TIA/carotid plaque 51 Retrospective, IIR, 1 center, blinded reading CTA 65 94 75 90 Breast (n = 2264) Ha et al,26 2019 Recurrence of BC/recurrence 47 Retrospective, IIR, 1 center, blinded reading Histopathology 94.1–96.1 97.9–98.3 37.8–43.8 99.9 Hegazy et al,27 2020 Breast papilloma/lesion detection 37 Retrospective, IIR, 1 center, blinded reading Histopathology 100 0, 58, 66.7 Kim et al,28 2022 History of BC/BI-RADS category, malignant vs benign 867 Retrospective, IIR, 1 center, blinded reading Histopathology 90 88.6–95.3 10–21 Kul et al,29 2014 Breast lesions/mass and nonmass lesions 267 Retrospective, IIR, 1 center, blinded reading Histopathology 85.7; 94.7 71.1; 79.8 76.7–89.2 Luczynska et al,30 2015 Suspicious lesion/lesion characterization 102 Retrospective, IIR, 1 center, blinded reading Histopathology 93 73 74 65 Pediconi et al,31 2013 Proven BC/lesion detection, characterization 72 Prospective, IIR, 3 centers, blinded reading Surgery, histopathology 82.3 Sardanelli et al,32 2016 Proven BC/malignancy detection 388 Prospective, phase III, 28 centers, blinded reading Histopathology, XRM, ultrasound 79.9–86.7 85.6–95 Sardanelli et al,33 2016 Proven BC/malignancy detection 390 Prospective, phase III, 39 centers, blinded reading Histopathology, XRM, ultrasound 85.5–89.0 82.8–91.8 Schmitz et al,34 2008 Breast lesion/lesion characterization 54 Prospective, IIR, 1 center, blinded reading Histopathology 100 74 86 76 100 Yüzkan et al,35 2021 Breast lesion/lesion characterization 40 Prospective, IIR, 1 center, unblinded reading Histopathology 100 77.4 74.5 100 Heart (n = 1312) Arai et al,36 2020 Multivessel CAD/stenosis detection 764 Prospective, phase III, 24 centers, blinded reading QCA stenosis ≥70% 78.9 86.8 87.1 69.7 91.4 Bettencourt et al,37 2013 Suspected CAD/stenosis detection 103 Prospective, IIR, 1 center, blinded reading ICA; FFR 89 88 88 85 91 Fenchel et al,38 2007 Suspected CAD/perfusion defects 25 Prospective, IIR, 1 center, blinded reading ICA 82–89 91–94 Grani et al,39 2022 ST-elevation myocardial infarction/LGE, MVO 48 Prospective, IIR, 1 center, blinded reading Percutaneous coronary intervention 76–78 67–74 30–81 70–94 Lurz et al,40 2016 Acute and chronic myocarditis/ECV, Lake Loise Criteria 129 Prospective, IIR, 1 center, blinded reading Endomyocardial biopsy 64–85 47–72 59–80 71–88 32–71 Manka et al,41 2015 CAD/myocardial perfusion 155 Prospective, IIR, 5 centers, blinded reading ICA, FFR 84.7 90.8 87.3 92.3 81.9 Palmisano et al,42 2020 Acute myocarditis/hyperemia, early T1 shortening ≥70% 45 Prospective, IIR, 2 centers, blinded reading Endomyocardial biopsy 93 100 95 Scheffel et al,43 2010 CAD/perfusion, LGE 43 Prospective, IIR, 1 center, blinded CTCA 89.7 100 93 100 82.4 Prostate (n = 543) Caglic et al,44 2022 Cancer/extracapsular extension 85 Retrospective, IIR; 1 center, blinded reading Histopathology 63.5 81.3 69.9 85.7 55.7 Drudi et al,45 2019 Suspected cancer/lesion detection 82 Prospective, IIR, 1 center, blinding not mentioned Histopathology 95.6 88.9 92.7 91.7 94.1 Engelhard et al,46 2014 Prostate index cancer/detection, characterization 88 Prospective, IIR, 1 center, blinded reading Histopathology 89 100 90 100 44 Hara et al,47 2018 Cancer/detection 94 Retrospective, IIR, 1 center, blinded reading Histopathology 91 87 89 91 87 Kang et al,48 2021 Cancer/lesions Likert 4–5 194 Retrospective, IIR, 1 center, blinded reading Histopathology 70.7–85.9 46.8–77.3 54.6–80.1 39.3–64.9 76.6–91.8 Kidney (n = 247) Defortescu et al,49 2017 Complex cysts/Bosniak ≥3 cysts 47 Prospective, IIR, 1 center, blinded reading Histology 71 91 85 77 88 Tombach et al,6 2008 Suspected renal lesions/detection, characterization 200 Prospective, phase III, multicenter, blinded reading CT 85.2 82.1 83.7 Liver (n = 433) Hammerstingl et al,50 2009 Known or suspected lesions/lesion classification 250 Prospective, phase III, 25 centers, blinded reading Truth panel 79.3 80.8 80.1 Jansen et al,51 2019 HCC, metastases/lesion classification 88 Retrospective, IIR; 1 center, reading