- Email: [email protected]
kg of gadoterate meglumine for cranial MRI
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Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI Katia Khouri Chalouhi b , Giacomo D.E. Papini a , Michele Bandirali b,∗ , Luca M. Sconfienza a,c , Giovanni Di Leo a , Francesco Sardanelli a,c a
Unità di Radiologia, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy Scuola di Specializzazione in Radiodiagnostica, Università degli Studi di Milano, Via Festa del Perdono 7, 20122 Milan, Italy c Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Morandi 30, 20097 San Donato Milanese, Milano, Italy b
a r t i c l e
i n f o
Article history: Received 21 January 2014 Received in revised form 17 March 2014 Accepted 22 March 2014 Keywords: Contrast-enhanced MRI Gadobenate dimeglumine Gadoterate meglumine Contrast material dose Brain MRI
a b s t r a c t Purpose: To retrospectively compare a reduced dose (RD) (0.075 mmol/kg) of gadobenate dimeglumine (RD-gadobenate) with standard single dose (SSD) (0.1 mmol/kg) of gadoterate meglumine (SSD-gadoterate) for cranial MRI. Materials and methods: Thirty-one patients (12 males; aged 52 ± 16 years) underwent cranial MRI with SSD-gadoterate and repeated the examination with RD-gadobenate after a median interval of 10 months. Signal-to-noise ratio (SNR) was obtained on contrast-enhanced images for enhancing lesions (n = 10) as well as for right and left transverse venous sinuses, internal carotid arteries, and parotid glands. Moreover, a consecutive series of 100 cranial MRI with SSD-gadoterate (49 males; aged 51 ± 19 years) was compared with a consecutive series of 100 cranial MRI with RD-gadobenate (45 males; aged 54 ± 18 years). Two blinded neuroradiologists (R1, R2) judged contrast enhancement as sufficient, good, or optimal. Wilcoxon, Mann–Whitney, 2 , and Cohen statistics were used. Results: At intraindividual analysis, median SNR ranged 57–88 for SSD-gadoterate and 79–99 for RDgadobenate, the latter being systematically higher, the difference being significant for both transverse venous sinuses (p ≤ 0.011), not significant for both internal carotid arteries and both parotid glands, and enhancing lesions (p ≤ 0.101). The two series of interindividual analysis were not significantly different for gender/age (p > 0.415). Contrast enhancement was optimal in 59% (R1) and 76% (R2) of patients using RD-gadobenate, in 39% (R1) and 49% (R2) of patients using SSD-gadoterate (p ≤ 0.016), with substantial reproducibility ( ≥ 0.606). Conclusion: Both analyses showed an equal or better contrast enhancement when using RD-gadobenate compared to SSD-gadoterate for routine cranial MRI. The high relaxivity of gadobenate allowed for a 25% dose reduction. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Gadolinium-based contrast agents (GBCAs) are used for cranial magnetic resonance imaging (MRI) mainly to detect the presence of injuries of the blood–brain barrier as well to detect and characterize enhancing lesions, such as primary or secondary neoplasms or
∗ Corresponding author. Tel.: +39 02 52774468; fax: +39 02 52774925. E-mail addresses: [email protected] (K. Khouri Chalouhi), [email protected] (G.D.E. Papini), [email protected] (M. Bandirali), io@lucasconfienza.it (L.M. Sconfienza), [email protected] (G. Di Leo), [email protected] (F. Sardanelli).
inflammatory lesions [1,2]. Moreover, GBCAs are also used to evaluate perfusion within focal lesions and normal or abnormal (e.g. ischemic) brain parenchyma [1]. Although rare, GBCAs can induce adverse events but these are seldom severe [3]. Moreover, studies have demonstrated a probable association between GBCA injection and the onset of nephrogenic systemic fibrosis in patients affected with acute or chronic renal disease [4]. Finally, the administration of GBCA is associated with a not negligible cost. Thus, strategies could be adopted in order to reduce the contrast dose without affecting contrast enhancement. One of the most commonly administered GBCA for cranial MRI is gadoterate meglumine (Gd-DOTA, Dotarem, Guerbet, Paris, France), usually dispensed at a standard single dose (SSD) of
http://dx.doi.org/10.1016/j.ejrad.2014.03.030 0720-048X/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030
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0.1 mmol/kg bodyweight [5]. This contrast material has a longitudinal relaxation rate similar to that of other standard-relaxivity GBCAs. In recent years, gadobenate dimeglumine (Gd-BOPTA, MultiHance, Bracco Imaging SpA, Milan, Italy) has been increasingly applied for routine MR exams thanks to its roughly two-fold higher longitudinal relaxivity compared to the other GBCAs [6,7]. This characteristic is due to a weak binding to plasmatic proteins, leading to a significantly higher reduction of T1relaxation time compared with that of standard relaxivity GBCAs [2]. In 2002, Schneider et al. [8] demonstrated that for liver MRI a dose of 0.05 mmol/kg of gadobenate dimeglumine provides similar diagnostic information when compared with a standard dose of 0.1 mmol/kg of gadopentetate dimeglumine. In a recent review, Giesel et al. [2] reported that a standard single dose (0.1 mmol/kg) of high-relaxivity contrast material provides greater contrast enhancement of brain lesions compared with equal doses of conventional standard-relaxivity contrast materials. Moreover, they suggested that the greatest advantage of high-relaxivity contrast materials could be the ability to lower the dose injected without sacrificing image quality or diagnostic confidence [2]. On the other hand, in a comparison of 0.05 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadodiamide for the detection of brain metastasis only one out of two blinded readers demonstrated the same diagnostic performance, however, this was an inter-individual comparison rather than an intra-individual comparison and was therefore subject to differences between treatment groups in terms of patient and lesion characteristics [9]. At our institution, 0.1 mmol/kg of gadoterate meglumine had been used for cranial MRI up to February 2011. Knowing that the same dosage of gadobenate dimeglumine would have resulted in a higher contrast enhancement of brain lesions [2,10] while a half dose may have resulted in lower diagnostic performance [9], we hypothesized that a 25% dose reduction may be at least equivalent to a full single dose of gadoterate meglumine. Thus, since March 2011, we have adopted an injection protocol adopting a reduced dose (RD) of 0.075 mmol/kg of gadobenate dimeglumine for routine cranial MRI. The aim of the current study was to compare the contrast enhancement obtained using 0.075 mmol/kg of gadobenate with that obtained using 0.1 mmol/kg of gadoterate for routine cranial MRI, using an intraindividual and interindividual retrospective design.
2. Materials and methods 2.1. Study population The local Ethics Committee approved this retrospective study. For the intraindividual comparison, we identified 31 consecutive patients (aged 52 ± 16 years, mean ± standard deviation; 12 males and 19 females) in our database who underwent cranial MRI twice, before and after the change of contrast material (February 2011), without any relevant clinical or imaging changes between the examinations, with a median interval between the two examinations of 10 months (interquartile interval 5–12 months). The first examination was performed using 0.1 mmol/kg gadoterate, while the second examination was performed using RD-gadobenate. For the interindividual comparison, we identified 100 consecutive patients (aged 51 ± 19 years; 49 males and 51 females) who underwent cranial MRI before February 2011 with SSD-gadoterate and 100 consecutive patients (aged 54 ± 18 years; 45 males and 55 females) who underwent a cranial MRI after February 2011 with RD-gadobenate.
2.2. Imaging protocol and image analysis All examinations were performed using a 1.5-T scanner (Magnetom Sonata Maestro Class, Siemens Medical Solution, Erlangen, Germany) and a volumetric head coil. Apart from the contrast material regimen, the imaging protocol did not differ among groups. All 231 patients were imaged at 4–5 min after contrast injection, as per our routine cranial MRI protocol, using axial T1-weighted spinecho sequences (TR 500–750 ms; TE 8–20 ms; pixel size 0.81 mm2 ; 1 excitation). For the intraindividual quantitative comparison, a circular region of interest (ROI) was placed on the following anatomical structures: • enhancing intracranial lesions (if any); • right and left transverse sinuses; • right and left internal carotid arteries (ICA) at the infra-petrosal level; • right and left parotid glands; • 10 enhancing lesions (two meningiomas and one for each of the following: rhabdomyosarcoma, pituitary macroadenoma, aneurysm of the internal carotid artery, demyelinating lesion, schwannoma of the eighth cranial nerve, radiation necrosis, metastasis from breast cancer, pineal cyst). Measurements were performed by a final year medical student, after a 3-month training period by a neuroradiologist with 3 years of experience. Circular ROIs were adapted in order to measure the signal intensity of the most enhancing part of the vascular or parenchymal site, using a ROI not smaller than nine pixels (7.29 mm2 ). A further ROI of the same size was placed in the air surrounding the patient’s head in a site free from artifacts along the phase-encoding axis. Each ROI was accurately placed in a homogeneous area avoiding image artifacts. The signal-to-noise ratio (SNR) of each site was calculated as the ratio between the signal intensity of that site and the standard deviation of the noise. For the between-group qualitative analysis, two independent neuroradiologists with three (R1) and eight (R2) years of experience, blinded to the contrast regimen and demographics, subjectively evaluated all images. They assigned a quality score to the contrast enhancement of the structures mentioned above as sufficient, good, or optimal. 2.3. Statistical analysis For intraindividual quantitative analysis, the median SNR obtained with the two contrast regimens were compared using the Wilcoxon signed-rank test. Data were expressed as median and interquartile interval. For interindividual qualitative analysis, age distribution was compared using Mann–Whitney U test. For each reader, the score assigned to the two patient groups was compared using the 2 test. Inter-reader reproducibility was estimated using the Cohen statistics. 3. Results 3.1. Intraindividual quantitative analysis At intraindividual quantitative analysis, the median SNR ranged from 57 to 88 for SSD-gadoterate and from 79 to 99 for RDgadobenate (Table 1). The SNR was systematically higher for all measured structures using RD-gadobenate, the differences being significant for the two transverse venous sinuses (p ≤ 0.011). Examples of the two contrast regimens are shown in Figs. 1 and 2.
Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030
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Table 1 Intraindividual comparison of signal-to-noise ratio obtained using 0.1 mmol/kg of gadoterate meglumine or 0.075 mmol/kg of gadobenate dimeglumine in 31 patients who underwent cranial MRI. Venous sinuses
Gadoterate 0.100 mmol/kg Gadobenate 0.075 mmol/kg pa
Internal carotid arteries
Parotid glands
Enhancing lesionsa
Right
Left
Right
Left
Right
Left
81 (60–96) 99(85–115) 0.002
80 (67–99) 96(82–117) 0.011
85(70–100) 95(87–107) 0.060
88(65–109) 97(82–106) 0.084
87 (77–95) 93(80–112) 0.101
83 (68–90) 92(80–103) 0.054
57 (44-90) 79 (67-89) 0.058
Data are median values with 25th and 75th percentiles in parentheses. a Wilcoxon signed-rank test for paired data.
Fig. 1. 69-year-old male who previously underwent partial resection of a meningioma in the left temporo-parietal region. (a) Axial T1-weighted image after intravenous administration of 0.1 mmol/kg of gadoterate meglumine. The measured signal-to-noise ratio was 48. (b) Axial T1-weighted image after intravenous administration of 0.075 mmol/kg of gadobenate dimeglumine. The measured signal-to-noise ratio was 77. A greater contrast enhancement of the residual meningioma (arrow) can be visually appreciated in b if compared with a.
Fig. 2. 65 year-old male affected with schwannoma of the right VIII cranial nerve (arrow). (a) Axial T1-weighted image after intravenous administration of 0.1 mmol/kg of gadoterate meglumine. The measured signal-to-noise ratio was 59. (b) Axial T1-weighted image after intravenous administration of 0.075 mmol/kg of gadobenate dimeglumine. The measured signal-to-noise ratio was 59. A similar lesion contrast enhancement can be visually appreciated in b if compared with a. Note the higher contrast enhancement of the nasal mucosa in b.
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Table 2 Interindividual comparison of qualitative scores obtained by two contrast regimens in two independent consecutive patient series who underwent cranial MRI. Reader 1
Sufficient Good Optimal Total pa a
Reader 2
Gadoterate 0.1 mmol/kg
Gadobenate 0.075 mmol/kg
Gadoterate 0.1 mmol/kg
Gadobenate 0.075 mmol/kg
13 (13%) 48 (48%) 39 (39%) 100 (100%) 0.016
7 (7%) 34 (34%) 59 (59%) 100 (100%)
10 (10%) 41 (41%) 49 (49%) 100 (100%) <0.001
4 (4%) 20 (20%) 76 (76%) 100 (100%)
2 test.
3.2. Interindividual qualitative analysis The two patient series were not significantly different in terms of age (p = 0.416) or gender (p = 0.571). For both readers, the score distribution associated with RD-gadobenate was shifted significantly toward higher scores than that associated with SSD-gadoterate (p < 0.001) (Table 2), optimal contrast enhancement (score 3) having been assigned to 39% (R1) or 49% (R2) of patients using SSD-gadoterate and to 59% (R1) or 76% (R2) of patients using RD-gadobenate, (p ≤ 0.016). Inter-reader reproducibility was substantial ( ≥ 0.606).
4. Discussion Gadobenate dimeglumine has been approved and used in Europe and around the world for MRI of the liver and central nervous system for many years. When used for non-liver imaging, it can be considered to have a two-compartment vascular/interstitial biodistribution, similar to other gadolinium-based contrast materials: it rapidly diffuses into the extracellular space and crosses the blood–brain barrier when breakdown occurs [11]. Recently it has also been approved for breast MRI, as a result of its very high diagnostic performance for breast cancer diagnosis [12,13] due to its higher relaxivity [14,15]. In this regard, the ability of gadobenate to weakly and transiently interact with human serum proteins (mainly albumin), reduces the tumbling rate of the molecule, which in turn shortens both the T1 and T2 relaxation times of water in blood [2,6]. The resulting r1 (1/T1) relaxivity for gadobenate is approximately 1.5- to 2-fold higher than that of gadopentetate dimeglumine at 1.5 T (7.9 l/mmol-1s-1 versus 3.9 l/mmol-1s-1) [7]. This characteristic allows gadobenate dimeglumine to achieve a higher diagnostic performance when compared with the same dose of other standard relaxivity contrast materials, such as gadoterate. In our study we compared the contrast enhancement obtained using RD-gadobenate with that obtained using SSD-gadoterate for cranial MRI. For the between-group quantitative analysis, contrast enhancement was at least equal for the two contrast regimens. In particular, the median SNR obtained using RD-gadobenate was superior to that obtained using SSD-gadoterate in each of the seven measurements, the difference being significant for the transverse venous sinuses (p ≤ 0.011). This direct intraindividual quantitative comparison shows that a 25% reduced dose of gadobenate does not affect contrast enhancement if compared with a standard single dose of gadoterate. Concerning the interindividual qualitative analysis, RDgadobenate provided superior contrast enhancement to that obtained with standard dose gadoterate. In this regard, the percentage of examinations evaluated as “optimal” (score 3) for contrast enhancement was 39% for gadoterate and 59% for gadobenate according to R1, and 49% and 76%, respectively, according to R2 (see Table 2). This comparison shows that the
visual contrast enhancement of RD-gadobenate was superior to that of SSD-gadoterate. Considering the huge number of contrast-enhanced cranial MRI examinations performed every year all over the world, the results of this study provide a strong evidence in favor of the routine use of a reduced dose of a high-relaxivity contrast material. The potential impact of a reduced dose might be seen in terms of patient safety, especially by reducing the accumulated dose for repeat MRI examinations, and in terms of cost reduction. In the current era of cost containment for health care systems, the old approach of using high-relaxivity contrast materials at a single 0.1 mmol/kg dose in order to see better in comparison with standard-relaxivity contrast materials can be modified in order to use a reduced dose of a high-relaxivity agent to see at least the same (possibly better). Our study has limitations. Firstly, the study was retrospective, with a median interval of 10 months between the two MRI examinations for the intraindividual comparison. However, we selected patients who reported no relevant clinical or imaging changes between the two examinations. A second consequence of the retrospective design is that the interindividual comparison was not performed after randomization of the two contrast regimens. However, we considered two series, each of them composed of 100 consecutive patients from our routine clinical practice, the first one when we were using SSD-gadoterate, the second one when we were using RD-gadobenate. Notably, our clinical setting for cranial MR imaging did not change in terms of patient type during the study period, before/after changing contrast regimen. As a consequence, the two series did not differ in terms of age or gender distribution. We acknowledge that a greater evidence in favor of the use of a reduced dose of high-relaxivity contrast material could be obtained with prospective intraindividual or randomized studies although this would entail relatively high research costs [16]. On the other hand, the current retrospective study provides preliminary evidence and was a spontaneous, non-company supported, research work conducted at an academic institution. Finally, the potential cost reduction should be evaluated country by country and center by center, depending on the ratio between the local cost of the high-relaxivity contrast material and that of the standard-relaxivity contrast material under consideration, which may be different. At our hospital, gadobenate dimeglumine has a similar price to that of low-relaxivity contrast materials, so that a 25% dose reduction results in a roughly 25% cost reduction. In conclusion, this study shows that in clinical brain MRI, the administration of 0.075 mmol/kg of gadobenate dimeglumine provides a contrast enhancement that is at least equivalent to that provided by the administration of 0.1 mmol/kg of gadoterate meglumine. This approach may have an impact in terms of patient safety and in terms of cost reduction and warrants further prospective investigations. Conflict of interest Francesco Sardanelli has received research grants from and is a member of the speakers’ bureau for Bracco Group, Milan,
Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030
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Italy. The remaining authors have no conflicts of interests to be declared. References [1] Smirniotopoulos JG, Murphy FM, Rushing EJ. Patterns of contrast enhancement in the brain and meninges. Radiographics 2007;27:525–51. [2] Giesel FL, Mehndiratta A, Essig M. High-relaxivity contrast-enhanced magnetic resonance neuroimaging: a review. Eur Radiol 2010;20:2461–74. [3] Bruder O, Schneider S, Nothnagel D. Acute adverse reactions to gadoliniumbased contrast agents in CMR: multicenter experience with 17,767 patients from the EuroCMR Registry. JACC Cardiovasc Imaging 2011;4:1171–6. [4] Thomsen HS, Morcos SK, Almén T, et al. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines. ESUR Contrast Medium Safety Committee. Eur Radiol 2013;23:307–18. [5] Essig M, Tartaro A, Tartaglione T. Enhancing lesions of the brain: intraindividual crossover comparison of contrast enhancement after gadobenate dimeglumine versus established gadolinium comparators. Acad Radiol 2006;13:744–51. [6] Cavagna FM, Maggioni F, Castelli PM. Gadolinium chelates with weak binding to serum proteins. A new class of high-efficiency, general purpose contrast agents for magnetic resonance imaging. Invest Radiol 1997;32:780–96. [7] Pintaske J, Martirosian P, Graf H, et al. Relaxivity of gadopentetate dimeglumine (Magnevist), gadobutrol (Gadovist), and gadobenate dimeglumine (MultiHance) in human blood plasma at 0.2, 1.5, and 3 Tesla. Invest Radiol 2006;41:213–21.
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[8] Schneider G, Maas R, Schultze Kool L, et al. Low dose gadobenate dimeglumine versus standard dose gadopentetate dimeglumine for contrast-enhanced magnetic resonance imaging of the liver. Invest Radiol 2003:85–94. [9] Runge VM, Parker JR, Donovan M. Double-blind, efficacy evaluation of gadobenate dimeglumine, a gadolinium chelate with enhanced relaxivity, in malignant lesions of the brain. Invest Radiol 2002;37:269–80. [10] Colosimo C, Knopp MV, Barreau X, et al. A comparison of Gd-BOPTA and Gd-DOTA for contrast enhanced MRI of intracranial tumours. Neuroradiology 2004;46:655–65. [11] Baleriaux D, Colosimo C, Ruscalleda J, et al. Magnetic resonance imaging of metastatic disease to the brain with gadobenate dimeglumine. Neuroradiology 2002;44:191–203. [12] Carbonaro LA, Pediconi F, Verardi N, et al. Breast MRI using a high-relaxivity contrast agent: an overview. AJR Am J Roentgenol 2011;196:942–55. [13] Martincich L, Faivre-Pierret M, Zechmann CM, et al. Multicenter, double-blind, randomized, intraindividual crossover comparison of gadobenate dimeglumine and gadopentetate dimeglumine for Breast MR imaging (DETECT Trial). Radiology 2011;258:396–408. [14] Sardanelli F, Fausto A, Esseridou A, et al. Gadobenate dimeglumine as a contrast agent for dynamic breast magnetic resonance imaging: effect of higher initial enhancement thresholds on diagnostic performance. Invest Radiol 2008;43:236–42. [15] Carbonaro LA, Verardi N, Di Leo G, et al. Handling a high relaxivity contrast material for dynamic breast MR imaging using higher thresholds for the initial enhancement. Invest Radiol 2010;45:114–20. [16] Sardanelli F, Hunink MG, Gilbert FJ, Di Leo G, Krestin GP. Evidence-based radiology: why and how? Eur Radiol 2010;20:1–15.
Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030
ARTICLE IN PRESS European Journal of Radiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI Katia Khouri Chalouhi b , Giacomo D.E. Papini a , Michele Bandirali b,∗ , Luca M. Sconfienza a,c , Giovanni Di Leo a , Francesco Sardanelli a,c a
Unità di Radiologia, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy Scuola di Specializzazione in Radiodiagnostica, Università degli Studi di Milano, Via Festa del Perdono 7, 20122 Milan, Italy c Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Morandi 30, 20097 San Donato Milanese, Milano, Italy b
a r t i c l e
i n f o
Article history: Received 21 January 2014 Received in revised form 17 March 2014 Accepted 22 March 2014 Keywords: Contrast-enhanced MRI Gadobenate dimeglumine Gadoterate meglumine Contrast material dose Brain MRI
a b s t r a c t Purpose: To retrospectively compare a reduced dose (RD) (0.075 mmol/kg) of gadobenate dimeglumine (RD-gadobenate) with standard single dose (SSD) (0.1 mmol/kg) of gadoterate meglumine (SSD-gadoterate) for cranial MRI. Materials and methods: Thirty-one patients (12 males; aged 52 ± 16 years) underwent cranial MRI with SSD-gadoterate and repeated the examination with RD-gadobenate after a median interval of 10 months. Signal-to-noise ratio (SNR) was obtained on contrast-enhanced images for enhancing lesions (n = 10) as well as for right and left transverse venous sinuses, internal carotid arteries, and parotid glands. Moreover, a consecutive series of 100 cranial MRI with SSD-gadoterate (49 males; aged 51 ± 19 years) was compared with a consecutive series of 100 cranial MRI with RD-gadobenate (45 males; aged 54 ± 18 years). Two blinded neuroradiologists (R1, R2) judged contrast enhancement as sufficient, good, or optimal. Wilcoxon, Mann–Whitney, 2 , and Cohen statistics were used. Results: At intraindividual analysis, median SNR ranged 57–88 for SSD-gadoterate and 79–99 for RDgadobenate, the latter being systematically higher, the difference being significant for both transverse venous sinuses (p ≤ 0.011), not significant for both internal carotid arteries and both parotid glands, and enhancing lesions (p ≤ 0.101). The two series of interindividual analysis were not significantly different for gender/age (p > 0.415). Contrast enhancement was optimal in 59% (R1) and 76% (R2) of patients using RD-gadobenate, in 39% (R1) and 49% (R2) of patients using SSD-gadoterate (p ≤ 0.016), with substantial reproducibility ( ≥ 0.606). Conclusion: Both analyses showed an equal or better contrast enhancement when using RD-gadobenate compared to SSD-gadoterate for routine cranial MRI. The high relaxivity of gadobenate allowed for a 25% dose reduction. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Gadolinium-based contrast agents (GBCAs) are used for cranial magnetic resonance imaging (MRI) mainly to detect the presence of injuries of the blood–brain barrier as well to detect and characterize enhancing lesions, such as primary or secondary neoplasms or
∗ Corresponding author. Tel.: +39 02 52774468; fax: +39 02 52774925. E-mail addresses: [email protected] (K. Khouri Chalouhi), [email protected] (G.D.E. Papini), [email protected] (M. Bandirali), io@lucasconfienza.it (L.M. Sconfienza), [email protected] (G. Di Leo), [email protected] (F. Sardanelli).
inflammatory lesions [1,2]. Moreover, GBCAs are also used to evaluate perfusion within focal lesions and normal or abnormal (e.g. ischemic) brain parenchyma [1]. Although rare, GBCAs can induce adverse events but these are seldom severe [3]. Moreover, studies have demonstrated a probable association between GBCA injection and the onset of nephrogenic systemic fibrosis in patients affected with acute or chronic renal disease [4]. Finally, the administration of GBCA is associated with a not negligible cost. Thus, strategies could be adopted in order to reduce the contrast dose without affecting contrast enhancement. One of the most commonly administered GBCA for cranial MRI is gadoterate meglumine (Gd-DOTA, Dotarem, Guerbet, Paris, France), usually dispensed at a standard single dose (SSD) of
http://dx.doi.org/10.1016/j.ejrad.2014.03.030 0720-048X/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030
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0.1 mmol/kg bodyweight [5]. This contrast material has a longitudinal relaxation rate similar to that of other standard-relaxivity GBCAs. In recent years, gadobenate dimeglumine (Gd-BOPTA, MultiHance, Bracco Imaging SpA, Milan, Italy) has been increasingly applied for routine MR exams thanks to its roughly two-fold higher longitudinal relaxivity compared to the other GBCAs [6,7]. This characteristic is due to a weak binding to plasmatic proteins, leading to a significantly higher reduction of T1relaxation time compared with that of standard relaxivity GBCAs [2]. In 2002, Schneider et al. [8] demonstrated that for liver MRI a dose of 0.05 mmol/kg of gadobenate dimeglumine provides similar diagnostic information when compared with a standard dose of 0.1 mmol/kg of gadopentetate dimeglumine. In a recent review, Giesel et al. [2] reported that a standard single dose (0.1 mmol/kg) of high-relaxivity contrast material provides greater contrast enhancement of brain lesions compared with equal doses of conventional standard-relaxivity contrast materials. Moreover, they suggested that the greatest advantage of high-relaxivity contrast materials could be the ability to lower the dose injected without sacrificing image quality or diagnostic confidence [2]. On the other hand, in a comparison of 0.05 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadodiamide for the detection of brain metastasis only one out of two blinded readers demonstrated the same diagnostic performance, however, this was an inter-individual comparison rather than an intra-individual comparison and was therefore subject to differences between treatment groups in terms of patient and lesion characteristics [9]. At our institution, 0.1 mmol/kg of gadoterate meglumine had been used for cranial MRI up to February 2011. Knowing that the same dosage of gadobenate dimeglumine would have resulted in a higher contrast enhancement of brain lesions [2,10] while a half dose may have resulted in lower diagnostic performance [9], we hypothesized that a 25% dose reduction may be at least equivalent to a full single dose of gadoterate meglumine. Thus, since March 2011, we have adopted an injection protocol adopting a reduced dose (RD) of 0.075 mmol/kg of gadobenate dimeglumine for routine cranial MRI. The aim of the current study was to compare the contrast enhancement obtained using 0.075 mmol/kg of gadobenate with that obtained using 0.1 mmol/kg of gadoterate for routine cranial MRI, using an intraindividual and interindividual retrospective design.
2. Materials and methods 2.1. Study population The local Ethics Committee approved this retrospective study. For the intraindividual comparison, we identified 31 consecutive patients (aged 52 ± 16 years, mean ± standard deviation; 12 males and 19 females) in our database who underwent cranial MRI twice, before and after the change of contrast material (February 2011), without any relevant clinical or imaging changes between the examinations, with a median interval between the two examinations of 10 months (interquartile interval 5–12 months). The first examination was performed using 0.1 mmol/kg gadoterate, while the second examination was performed using RD-gadobenate. For the interindividual comparison, we identified 100 consecutive patients (aged 51 ± 19 years; 49 males and 51 females) who underwent cranial MRI before February 2011 with SSD-gadoterate and 100 consecutive patients (aged 54 ± 18 years; 45 males and 55 females) who underwent a cranial MRI after February 2011 with RD-gadobenate.
2.2. Imaging protocol and image analysis All examinations were performed using a 1.5-T scanner (Magnetom Sonata Maestro Class, Siemens Medical Solution, Erlangen, Germany) and a volumetric head coil. Apart from the contrast material regimen, the imaging protocol did not differ among groups. All 231 patients were imaged at 4–5 min after contrast injection, as per our routine cranial MRI protocol, using axial T1-weighted spinecho sequences (TR 500–750 ms; TE 8–20 ms; pixel size 0.81 mm2 ; 1 excitation). For the intraindividual quantitative comparison, a circular region of interest (ROI) was placed on the following anatomical structures: • enhancing intracranial lesions (if any); • right and left transverse sinuses; • right and left internal carotid arteries (ICA) at the infra-petrosal level; • right and left parotid glands; • 10 enhancing lesions (two meningiomas and one for each of the following: rhabdomyosarcoma, pituitary macroadenoma, aneurysm of the internal carotid artery, demyelinating lesion, schwannoma of the eighth cranial nerve, radiation necrosis, metastasis from breast cancer, pineal cyst). Measurements were performed by a final year medical student, after a 3-month training period by a neuroradiologist with 3 years of experience. Circular ROIs were adapted in order to measure the signal intensity of the most enhancing part of the vascular or parenchymal site, using a ROI not smaller than nine pixels (7.29 mm2 ). A further ROI of the same size was placed in the air surrounding the patient’s head in a site free from artifacts along the phase-encoding axis. Each ROI was accurately placed in a homogeneous area avoiding image artifacts. The signal-to-noise ratio (SNR) of each site was calculated as the ratio between the signal intensity of that site and the standard deviation of the noise. For the between-group qualitative analysis, two independent neuroradiologists with three (R1) and eight (R2) years of experience, blinded to the contrast regimen and demographics, subjectively evaluated all images. They assigned a quality score to the contrast enhancement of the structures mentioned above as sufficient, good, or optimal. 2.3. Statistical analysis For intraindividual quantitative analysis, the median SNR obtained with the two contrast regimens were compared using the Wilcoxon signed-rank test. Data were expressed as median and interquartile interval. For interindividual qualitative analysis, age distribution was compared using Mann–Whitney U test. For each reader, the score assigned to the two patient groups was compared using the 2 test. Inter-reader reproducibility was estimated using the Cohen statistics. 3. Results 3.1. Intraindividual quantitative analysis At intraindividual quantitative analysis, the median SNR ranged from 57 to 88 for SSD-gadoterate and from 79 to 99 for RDgadobenate (Table 1). The SNR was systematically higher for all measured structures using RD-gadobenate, the differences being significant for the two transverse venous sinuses (p ≤ 0.011). Examples of the two contrast regimens are shown in Figs. 1 and 2.
Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030
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Table 1 Intraindividual comparison of signal-to-noise ratio obtained using 0.1 mmol/kg of gadoterate meglumine or 0.075 mmol/kg of gadobenate dimeglumine in 31 patients who underwent cranial MRI. Venous sinuses
Gadoterate 0.100 mmol/kg Gadobenate 0.075 mmol/kg pa
Internal carotid arteries
Parotid glands
Enhancing lesionsa
Right
Left
Right
Left
Right
Left
81 (60–96) 99(85–115) 0.002
80 (67–99) 96(82–117) 0.011
85(70–100) 95(87–107) 0.060
88(65–109) 97(82–106) 0.084
87 (77–95) 93(80–112) 0.101
83 (68–90) 92(80–103) 0.054
57 (44-90) 79 (67-89) 0.058
Data are median values with 25th and 75th percentiles in parentheses. a Wilcoxon signed-rank test for paired data.
Fig. 1. 69-year-old male who previously underwent partial resection of a meningioma in the left temporo-parietal region. (a) Axial T1-weighted image after intravenous administration of 0.1 mmol/kg of gadoterate meglumine. The measured signal-to-noise ratio was 48. (b) Axial T1-weighted image after intravenous administration of 0.075 mmol/kg of gadobenate dimeglumine. The measured signal-to-noise ratio was 77. A greater contrast enhancement of the residual meningioma (arrow) can be visually appreciated in b if compared with a.
Fig. 2. 65 year-old male affected with schwannoma of the right VIII cranial nerve (arrow). (a) Axial T1-weighted image after intravenous administration of 0.1 mmol/kg of gadoterate meglumine. The measured signal-to-noise ratio was 59. (b) Axial T1-weighted image after intravenous administration of 0.075 mmol/kg of gadobenate dimeglumine. The measured signal-to-noise ratio was 59. A similar lesion contrast enhancement can be visually appreciated in b if compared with a. Note the higher contrast enhancement of the nasal mucosa in b.
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Table 2 Interindividual comparison of qualitative scores obtained by two contrast regimens in two independent consecutive patient series who underwent cranial MRI. Reader 1
Sufficient Good Optimal Total pa a
Reader 2
Gadoterate 0.1 mmol/kg
Gadobenate 0.075 mmol/kg
Gadoterate 0.1 mmol/kg
Gadobenate 0.075 mmol/kg
13 (13%) 48 (48%) 39 (39%) 100 (100%) 0.016
7 (7%) 34 (34%) 59 (59%) 100 (100%)
10 (10%) 41 (41%) 49 (49%) 100 (100%) <0.001
4 (4%) 20 (20%) 76 (76%) 100 (100%)
2 test.
3.2. Interindividual qualitative analysis The two patient series were not significantly different in terms of age (p = 0.416) or gender (p = 0.571). For both readers, the score distribution associated with RD-gadobenate was shifted significantly toward higher scores than that associated with SSD-gadoterate (p < 0.001) (Table 2), optimal contrast enhancement (score 3) having been assigned to 39% (R1) or 49% (R2) of patients using SSD-gadoterate and to 59% (R1) or 76% (R2) of patients using RD-gadobenate, (p ≤ 0.016). Inter-reader reproducibility was substantial ( ≥ 0.606).
4. Discussion Gadobenate dimeglumine has been approved and used in Europe and around the world for MRI of the liver and central nervous system for many years. When used for non-liver imaging, it can be considered to have a two-compartment vascular/interstitial biodistribution, similar to other gadolinium-based contrast materials: it rapidly diffuses into the extracellular space and crosses the blood–brain barrier when breakdown occurs [11]. Recently it has also been approved for breast MRI, as a result of its very high diagnostic performance for breast cancer diagnosis [12,13] due to its higher relaxivity [14,15]. In this regard, the ability of gadobenate to weakly and transiently interact with human serum proteins (mainly albumin), reduces the tumbling rate of the molecule, which in turn shortens both the T1 and T2 relaxation times of water in blood [2,6]. The resulting r1 (1/T1) relaxivity for gadobenate is approximately 1.5- to 2-fold higher than that of gadopentetate dimeglumine at 1.5 T (7.9 l/mmol-1s-1 versus 3.9 l/mmol-1s-1) [7]. This characteristic allows gadobenate dimeglumine to achieve a higher diagnostic performance when compared with the same dose of other standard relaxivity contrast materials, such as gadoterate. In our study we compared the contrast enhancement obtained using RD-gadobenate with that obtained using SSD-gadoterate for cranial MRI. For the between-group quantitative analysis, contrast enhancement was at least equal for the two contrast regimens. In particular, the median SNR obtained using RD-gadobenate was superior to that obtained using SSD-gadoterate in each of the seven measurements, the difference being significant for the transverse venous sinuses (p ≤ 0.011). This direct intraindividual quantitative comparison shows that a 25% reduced dose of gadobenate does not affect contrast enhancement if compared with a standard single dose of gadoterate. Concerning the interindividual qualitative analysis, RDgadobenate provided superior contrast enhancement to that obtained with standard dose gadoterate. In this regard, the percentage of examinations evaluated as “optimal” (score 3) for contrast enhancement was 39% for gadoterate and 59% for gadobenate according to R1, and 49% and 76%, respectively, according to R2 (see Table 2). This comparison shows that the
visual contrast enhancement of RD-gadobenate was superior to that of SSD-gadoterate. Considering the huge number of contrast-enhanced cranial MRI examinations performed every year all over the world, the results of this study provide a strong evidence in favor of the routine use of a reduced dose of a high-relaxivity contrast material. The potential impact of a reduced dose might be seen in terms of patient safety, especially by reducing the accumulated dose for repeat MRI examinations, and in terms of cost reduction. In the current era of cost containment for health care systems, the old approach of using high-relaxivity contrast materials at a single 0.1 mmol/kg dose in order to see better in comparison with standard-relaxivity contrast materials can be modified in order to use a reduced dose of a high-relaxivity agent to see at least the same (possibly better). Our study has limitations. Firstly, the study was retrospective, with a median interval of 10 months between the two MRI examinations for the intraindividual comparison. However, we selected patients who reported no relevant clinical or imaging changes between the two examinations. A second consequence of the retrospective design is that the interindividual comparison was not performed after randomization of the two contrast regimens. However, we considered two series, each of them composed of 100 consecutive patients from our routine clinical practice, the first one when we were using SSD-gadoterate, the second one when we were using RD-gadobenate. Notably, our clinical setting for cranial MR imaging did not change in terms of patient type during the study period, before/after changing contrast regimen. As a consequence, the two series did not differ in terms of age or gender distribution. We acknowledge that a greater evidence in favor of the use of a reduced dose of high-relaxivity contrast material could be obtained with prospective intraindividual or randomized studies although this would entail relatively high research costs [16]. On the other hand, the current retrospective study provides preliminary evidence and was a spontaneous, non-company supported, research work conducted at an academic institution. Finally, the potential cost reduction should be evaluated country by country and center by center, depending on the ratio between the local cost of the high-relaxivity contrast material and that of the standard-relaxivity contrast material under consideration, which may be different. At our hospital, gadobenate dimeglumine has a similar price to that of low-relaxivity contrast materials, so that a 25% dose reduction results in a roughly 25% cost reduction. In conclusion, this study shows that in clinical brain MRI, the administration of 0.075 mmol/kg of gadobenate dimeglumine provides a contrast enhancement that is at least equivalent to that provided by the administration of 0.1 mmol/kg of gadoterate meglumine. This approach may have an impact in terms of patient safety and in terms of cost reduction and warrants further prospective investigations. Conflict of interest Francesco Sardanelli has received research grants from and is a member of the speakers’ bureau for Bracco Group, Milan,
Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030
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Please cite this article in press as: Khouri Chalouhi K, et al. Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. Eur J Radiol (2014), http://dx.doi.org/10.1016/j.ejrad.2014.03.030