Clinical Imaging 120 (2025) 110420

Contents lists available at ScienceDirect

Clinical Imaging
journal homepage: www.elsevier.com/locate/clinimag

Breast Imaging

A review of gadolinium-based contrast agents in the setting of repeated MRI

for high risk breast cancer screening
Kelcie Foshag , Apostolos John Tsiouris , Martin Prince , Melissa Reichman *
Weill Cornell Medicine at New York-Presbyterian Hospital, 525 East 68th Street, New York, NY 10065, United States of America

A R T I C L E I N F O A B S T R A C T

Keywords: Women who are considered high risk for breast cancer are recommended to undergo supplemental breast cancer
Screening breast MRI screening annually with MRI. There are primarily three safety concerns associated with gadolinium-based
Gadopiclenol contrast agents which include allergic reactions, nephrogenic systemic fibrosis and gadolinium deposition. In
Gadobutrol versus gadoterate
this review, we discuss how these risks are affected by molecular structure, will specifically review the difference
MRI contrast
between the two commonly used agents, gadobutrol and gadoterate, and discuss the most recent FDA approved
contrast agent on the market, gadopiclenol.

1. Introduction 2. Allergic reactions

Women who are considered high risk for breast cancer, defined as a Katayama et al. published a landmark study in 1990 showing how
20 % or greater lifetime risk, are recommended to undergo supplemental nonionic iodinated contrast agents have fewer contrast reactions
breast cancer screening annually with MRI.1 Approximately 15 % of compared to ionic agents.5 This made sense because ionic agents
women between the ages of 35 and 79 years in the United States meet dissociate into positively and negatively charged species, doubling the
this high-risk criteria for breast cancer.2 With the recommendation for particle count, increasing viscosity, and increasing osmolality, which are
beginning breast MRI screening at 25 to 30 years of age, this means all associated with triggering acute reactions. So, when the first GBCA
women may be receiving 40 to 50+ breast MRIs within their lifetime. In was introduced, gadopentetate dimeglumine (Magnevist, Bayer Scher­
addition to high risk individuals, the most recent ACR appropriateness ing Pharma), an ionic linear GBCA, there was a push to develop nonionic
guidelines include screening breast MRI for women with average or GBCAs. Gadodiamide (Omniscan, GE Healthcare), the first nonionic
intermediate risk with dense breasts.3 An estimated 43 % of women, 40 linear GBCA to be approved, had a substantially lower reaction rate
to 74 years of age, have dense breasts, and thus may receive 30 to 40 (0.15 %) and quickly became nearly as popular as gadopentetate
MRIs over their lifetime.4 While MRI has the safety advantage of no dimeglumine (reaction rate 0.5 %).6 Then a nonionic macrocyclic agent,
ionizing radiation exposure, it does require injection of a gadolinium- gadoteridol (Prohance, Bracco) was introduced, defying theory and
based contrast agent (GBCA) with safety issues that need to be consid­ causing a higher rate of reactions (1.6 %).6 These were attributed to
ered. There are primarily three safety concerns associated with GBCAs: manufacturing issues and impurities and this agent ultimately never
allergic reactions, nephrogenic systemic fibrosis (NSF), and gadolinium attained substantial market share. Gadoterate meglumine, a macrocyclic
deposition. In this review we discuss how these risks are affected by the ionic GBCA and gadobutrol were then introduced, both with similar
molecular structure considering ionicity, viscosity, and structure (linear acute reaction rates as gadoteridol, the other macrocyclic GBCA
versus macrocyclic) and implications for maximizing safety in breast (gadoterate meglumine 0.9 % and gadobutrol 1.6 %).6 However,
MRI. We will specifically review the difference between the two most gadoterate dimeglumine had higher thermodynamic stability and
commonly used contrast agents, gadobutrol (Gadavist, Bayer Schering gadobutrol had higher T1 relaxivity making them preferred.
Pharma) and gadoterate meglumine (Dotarem, Guerbet) and discuss the
most recent FDA approved contrast agent on the market, gadopiclenol
(Vueway, Bracco and Elucirem, Guerbet).

* Corresponding author.
E-mail addresses: [email protected] (K. Foshag), [email protected] (A.J. Tsiouris), [email protected] (M. Prince), mdb9013@med.
cornell.edu (M. Reichman).

https://doi.org/10.1016/j.clinimag.2025.110420
Received 2 December 2024; Received in revised form 26 January 2025; Accepted 2 February 2025
Available online 3 February 2025
0899-7071/Published by Elsevier Inc.
K. Foshag et al. Clinical Imaging 120 (2025) 110420

Table 1 et al. showed this increased T1 signal was indeed gadolinium on post­
ACR manual classification of gadolinium-based contrast agents.13 mortem studies of humans and animals.11,12 There is ongoing research
Group I contrast agents being performed on the topic but to date there is no evidence of any
clinical effects or adverse outcomes of gadolinium deposition in the
• Gadodiamide (Omniscan)
• Gadopentate dimeglumine (Magnevist) brain.11 However, the literature on this topic has made patients more
• Gadoversetamide (OptiMARK) aware and concerned about the long-term effects of receiving multiple
contrast enhanced MRIs and has drawn attention to the specific types of
GBCAs used in breast imaging. Most linear GBCAs have a higher likeli­
Group II contrast agent hood of depositing in the brain, so macrocyclic agents are primarily used
• Gadobenate dimeglumine (MultiHance)
today to minimize deposition.13,14 There has been a recent trend of
• Gadobutrol (Gadavist) patients at our institution requesting gadoterate meglumine over
• Gadoterate (Dotarem) gadobutrol for screening breast MRI. These requests may be related to
• Gadoteridol (Prohance) marketing strategies about gadolinium deposition and their presence on
Gadopiclenol (Elucirem/Vueway)
•
social media.
• Gadoxetate disodium (Eovist)
Gadobutrol and gadoterate meglumine are both macrocyclic GBCAs
(Fig. 1). The main differences between the two agents are the electric
3. Nephrogenic systemic fibrosis (NSF) charge (gadobutrol is nonionic and gadoterate meglumine is ionic), T1
relaxivity (gadobutrol 5.2 L/mmol s at 1.5 T vs. gadoterate meglumine
Although the original GBCA, gadopentetate dimeglumine was 3.9 L/mmol s at 1.5 T), and the concentration (gadobutrol 1.0 mmol/mL
approved at a low dose of 0.1 mMol/kg, the nonionic linear GBCA vs. gadoterate 0.5 mmol/mL) (Table 2). The effect of these properties
gadodiamide was approved for triple dose, 0.3mMol/kg even though its regarding gadolinium deposition in the brain is not clear with limited
nonionic molecular structure did not bind the chelator as tightly as the research directly on this point. One study out of Switzerland compares
ionic or macrocyclic agents. When cases of a rare nephrogenic fibrosing gadolinium deposition in rats between the three macrocyclic agents:
dermopathy emerged beginning in 2001 shortly after the approval of gadobutrol, gadoterate, and gadoteridol. This study found significantly
gadodiamide at high doses, the etiology was a mystery. In 2006, an less gadolinium deposition in the cerebrum and cerebellum in the rats
observant Austrian nephrologist reported a cluster of 5 cases all occur­ exposed to gadoteridol compared to gadoterate or gadobutrol. This was
ring shortly after injections of high doses of the nonionic linear GBCA, speculated to be due to lower viscosity of gadoteridol resulting in faster
gadodiamide.7 Interestingly, he did not realize that there were different elimination reducing the time available for deposition (gadoteridol
types of GBCA; in his original paper he reported using Gd-DTPA (Mag­ viscosity 1.3 mPa s, gadobutrol viscosity 5.0 mPa s, and gadoterate 2.0
nevist) and later published an erratum indicating his dialysis patients mPa s) (Table 2). Gadolinium deposition in the cerebrum and cere­
that developed NSF actually received Gd-DTPA-BMA (gadodiamide). bellum was similar for gadoterate and gadobutrol.15
With the association of NSF in end stage renal disease patients on Differences in T1 relaxivity and concentrations of gadobutrol versus
dialysis to gadodiamide now suspected, additional reports quickly gadoterate meglumine have motivated research on enhancement and
emerged.8 The disease was found to involve more organs than just skin clinical outcomes of these two contrast agents. A randomized, intra-
and was renamed to nephrogenic systemic fibrosis (NSF). NSF was iso­ individual study directly comparing these two GBCA demonstrated
lated to patients with renal impairment, GFR < 15, in acute renal failure that gadobutrol had a significantly higher peak enhancement on breast
or on dialysis receiving high doses of the GBCAs that had weaker binding MRI compared with gadoterate meglumine.16 This was again demon­
linear structures and especially the nonionic, linear structure. Currently, strated in a study directly comparing the two agents for benign prostatic
NSF has been virtually eliminated with the use of Group II contrast hyperplasia (BPH) nodules on prostate MRI.17 While the peak
agents (Table 1).8 In a systematic review and meta-analysis of 4931 enhancement is higher for gadobutrol, most studies reveal no superior
patients with stage 4 or 5 chronic kidney disease with or without dialysis clinical outcome between the two agents. A 2013 study found that the
and administration of an unconfounded group II GBCA, the incidence of use of gadoterate meglumine and gadobutrol were similar in the final
NSF was zero, and risk is likely <0.07 %.9 classification of breast lesions and diagnostic accuracy.18 This is
consistent with additional studies demonstrating non-inferiority of
4. Gadolinium deposition gadoterate meglumine to gadobutrol in other non-breast MRIs including
detection of peripheral artery disease,19 osteomyelitis,20 and primary
Gadolinium deposition was brought into attention by Kanda et al. in brain tumors.21
2013 reporting increased T1 signal in the dentate nucleus and globus A promising new nonionic macrocyclic GBCA, gadopiclenol, was
pallidus accumulating after multiple GBCA enhanced MRIs.10 McDonald FDA approved in September 2022 (Fig. 1). Advantages of gadopiclenol

Fig. 1. Macrocyclic GBCA molecular structures.29,30

2
K. Foshag et al. Clinical Imaging 120 (2025) 110420

Table 2
Properties of gadolinium based contrast agents.27,28
Ionicity Structure T1 relaxivity in plasma, 1.5 T (L/mmol s− 1) Viscosity (mPa s at 37 ◦ C) Kinetic stability

Gadobutrol (Gadavist) Nonionic Macrocyclic 5.2 5.0 18 h

Gadoterate meglumine (Dotarem) Ionic Macrocyclic 3.6 2.4 4 days
Gadoteridol (Prohance) Nonionic Macrocyclic 4.1 1.3 4h
Gadopentate (Magnevist) Ionic Linear 4.1 2.9 <5 s
Gadodiamide (Omniscan) Nonionic Linear 4.5 1.4 <5 s
Gadopiclenol (Vueway/Elucirem) Nonionic Macrocyclic 12.2 7.6 20 days

include a low molecular weight to facilitate rapid elimination compa­ 4 Sprague BL, Gangnon RE, Burt V, et al. Prevalence of mammographically dense
breasts in the United States. J Natl Cancer Inst 2014;106(10). https://doi.org/
rable to other GBCA, high stability, and substantially higher relaxivity
10.1093/jnci/dju255.
than existing macrocyclic agents (11.6 mmol sec) (Table 1). This higher 5 Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse
relaxivity allows a 50 % reduced dose of 0.05 mmol/kg (standard reactions to ionic and nonionic contrast media. A report from the Japanese
contrast agents are dosed at 0.1 mmol/kg) which was demonstrated in committee on the safety of contrast media. Radiology 1990;175(3):621–8. https://
doi.org/10.1148/radiology.175.3.2343107.
the PROMISE22 and PICTURE23 trials, where gadopiclenol was found to 6 Behzadi AH, Zhao Y, Farooq Z, Prince MR. Immediate allergic reactions to
be noninferior to gadobutrol in detecting lesions in the head and neck, gadolinium-based contrast agents: a systematic review and meta-analysis. Radiology
breast, thorax, abdomen, pelvis, and musculoskeletal system at this 2018;286:471–82.
7 Grobner T. Gadolinium—a specific trigger for the development of nephrogenic
lower dose. In a study comparing gadolinium deposition in rats between fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis
gadopiclenol, gadobutrol, and gadodiamide, Gadopiclenol's distribution Transplantation 2006;21(6):1745. https://doi.org/10.1093/ndt/gfl294.
and washout kinetics in the brain were similar to gadobutrol.24 The 8 Attari H, Cao Y, Elmholdt TR, Zhao Y, Prince MR. A systematic review of 639 patients
with biopsy-confirmed nephrogenic systemic fibrosis. Radiology 2019;292:376–86.
American College of Radiology classified gadopiclenol as a Group II https://doi.org/10.1148/radiol.2019182916.
agent with negligible risk of nephrogenic systemic fibrosis (Table 1).25 9 Woolen SA, Shankar PR, Gagnier JJ, MacEachern MP, Singer L, Davenport MS. Risk
This new GBCA contrast agent was developed in response to the need of of nephrogenic systemic fibrosis in patients with stage 4 or 5 chronic kidney disease
receiving a group II gadolinium-based contrast agent. JAMA Intern Med 2020;180
reducing the administered dose of gadolinium to minimize potential (2):223–30. https://doi.org/10.1001/jamainternmed.2019.5284.
risks associated with gadolinium exposure, while maintaining high level 10 Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the
of diagnostic efficacy.26 So if a woman is anticipating having 40 breast dentate nucleus and globus pallidus on unenhanced T1-weighted MR images:
relationship with increasing cumulative dose of a gadolinium-based contrast
MRIs over a lifetime, using gadopiclenol is as if this number is reduced to
material. Radiology 2013;270(3):834–41. https://doi.org/10.1148/
20 in terms of the molar amount of gadolinium being administered. radiol.13131669.
In conclusion, our review of the two macrocyclic contrast agents, 11 McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition
gadobutrol and gadoterate, demonstrate similar safety profiles and after contrast-enhanced MR imaging. Radiology 2015;275(3):772–82. https://doi.
org/10.1148/radiol.15150025.
clinical efficacy. Gadobutrol is primarily used at our institution but 12 Sardanelli F, et al. Gadolinium retention and breast MRI screening: more harm than
when patients specifically ask for gadoterate, we feel it is reasonable to good? Am J Roentgenol 2019;214(2):324–7. https://doi.org/10.2214/ajr.19.21988.
accommodate their request since we have both on formulary. With the 13. Contrast manual (2024) Contrast Manual | American College of Radiology. Available
at: https://www.acr.org/Clinical-Resources/Contrast-Manual (Accessed: 14
potential of the newest contrast agent, gadopiclenol, recently on the September 2024).
market, we may be able to lower the dose of contrast used, although it is 14 Lenkinski RE. ‘Gadolinium deposition and retention in the brain: should we be
questionable whether this will result in any benefit for our patients concerned?’, Radiology: cardiothoracic. Imaging 2019;1(3). https://doi.org/10.1148/
ryct.2019190104.
receiving repeated contrast enhanced MRIs. 15 Bussi S, et al. Differences in gadolinium retention after repeated injections of
macrocyclic MR contrast agents to rats. J Magn Reson Imaging 2017;47(3):746–52.
https://doi.org/10.1002/jmri.25822.
CRediT authorship contribution statement
16 Fallenberg EM, et al. Intraindividual, randomized comparison of the macrocyclic
contrast agents gadobutrol and gadoterate meglumine in breast magnetic resonance
Kelcie Foshag: Writing – review & editing, Writing – original draft. imaging. Eur Radiol 2014;25(3):837–49. https://doi.org/10.1007/s00330-014-
3426-0.
Apostolos John Tsiouris: Writing – review & editing, Validation, Re­
17 Lee CH, et al. Dynamic contrast-enhanced MR imaging of the prostate:
sources. Martin Prince: Writing – review & editing, Writing – original Intraindividual comparison of gadoterate Meglumine and gadobutrol. Eur Radiol
draft. Melissa Reichman: Writing – review & editing, Writing – original 2019;29(12):6982–90. https://doi.org/10.1007/s00330-019-06321-6.
draft, Supervision. 18 Renz DM, et al. Comparison of gadoteric acid and gadobutrol for detection as well as
morphologic and dynamic characterization of lesions on breast dynamic contrast-
enhanced magnetic resonance imaging. Invest Radiol 2014;49(7):474–84. https://
doi.org/10.1097/rli.0000000000000039.
Declaration of competing interest 19 Loewe C, et al. Mr angiography at 3 T of peripheral arterial disease: a randomized
prospective comparison of gadoterate meglumine and gadobutrol. Am J Roentgenol
2015;204(6):1311–21. https://doi.org/10.2214/ajr.14.12604.
No competing interest or financial disclosures. 20 Scott LJ. Gadobutrol: a review in contrast-enhanced MRI and MRA. Clin Drug
Investig 2018;38(8):773–84. https://doi.org/10.1007/s40261-018-0674-9.
21. Maravilla, K.R. et al. (2017) Comparison of gadoterate meglumine and gadobutrol in
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