Use of Gadolinium Based Contrast Agents – What, Why and What Is Next?

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https://www.ia-grp.com/views/gadolinium-mri-clinical-trials/

On the 29 November 2017, Dr. McDonald and colleagues find that there is no evidence that accumulation in the brain of the element gadolinium speeds cognitive decline or causes neurologic harm, according to a new study presented today at the annual meeting of the Radiological Society of North America (RSNA). The researchers used the Mayo Clinic Study of Aging (MCSA), the world's largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function. 

All participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals. Neurologic and neurocognitive scores were compared using standard methods between MCSA patients with no history of prior gadolinium exposure and those who underwent prior MRI with gadolinium-based contrast agents. Progression from normal cognitive status to mild cognitive impairment and dementia was assessed using multistate Markov model analysis.

The study included 4,261 cognitively normal men and women, between the ages of 50 and 90 with a mean age of 72. Mean length of study participation was 3.7 years. Of the 4,261 participants, 1,092 (25.6 percent) had received one or more doses of gadolinium-based contrast agents, with at least one participant receiving as many as 28 prior doses. Median time since first gadolinium exposure was 5.6 years.

After adjusting for age, sex, education level, baseline neurocognitive performance, and other factors, gadolinium exposure was not a significant predictor of cognitive decline, dementia, diminished neuropsychological performance or diminished motor performance. No dose-related effects were observed among these metrics.

Gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia in this study group.

"Right now there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues," Dr. McDonald said. "This study provides useful data that at the reasonable doses 95 percent of the population is likely to receive in their lifetime, there is no evidence at this point that gadolinium retention in the brain is associated with adverse clinical outcomes."

source: https://www.sciencedaily.com/releases/2017/11/171129090434.htm

On the 11 September, 2017 FDA advisory committee voted 13-1, with one abstention, to recommend a new warning for gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging.  

The FDA made a distinction between macrocyclic and linear GBCAs, noting the higher stability of the macrocyclics may cause them to "wash out" of the body; but the agency stressed that both agents leave behind deposits of gadolinium. Agency leadership asked the committee for advice on how to weigh recent findings of gadolinium retention in the brain and other organs, and how to minimize potential risks moving forward.

Virtually all committee members agreed that the evidence of retention in patients, to date, doesn't indicate a definitive causal relationship with an array of symptoms reported in the FDA's database and medical literature, beyond previously identified concerns for kidney patients (current labeling already includes a boxed warning and contraindications for this population).

The members voted unanimously to recommend the FDA consider requiring industry conduct more research to help the agency determine if regulatory action "including withdrawal of approval and restriction of indicated populations" is necessary.

Jeffrey Brent, MD, PhD, of the University of Pennsylvania, who backed the new warning, described the latest evidence of problems in patients without a serious renal condition as "anecdotal data." However, "there clearly is concern and people need to know.

speak to our advisors or read more:  https://www.medpagetoday.com/radiology/diagnosticradiology/67811

On the 24th May 2017: Further important update following a series of disturbing findings that surfaced in 2013 indicating that traces of gadolinium were detectable in the brains of patients who had received MRI contrast, in some cases years after the scans occurred. FDA investigation finds no evidence of negative health effects occuring due to Gadolinium remaining in body after MRI Contrast administration. In a safety announcement, the FDA stated that its review had identified "no harmful effects to date" from brain retention of gadolinium-based contrast agents (GBCAs). The agency, therefore, concluded that it was not necessary to place any new restrictions on gadolinium contrast products.

Note that the FDA acknowledged that its review found that linear gadolinium agents were responsible for depositing more gadolinium than macrocyclic agents, but said that no health effects were associated with either class of agents.

On the 22nd May 2017, after a nearly 2-year study, the US Food and Drug Administration (FDA) announced that it has not found any evidence of adverse events from the brain's retention of gadolinium after MRI that uses gadolinium-based contrast agents (GBCAs). Accordingly, the FDA will not restrict the use of GBCAs, but it will continue to study their safety, the agency said in a news release. Read more: https://www.imageanalysis.org.uk/general/mri-gadolinium

On the 4th April 2017 American Society of Radiology (ACR) published a letter in response to the PRAC recommendations of suspending some of the linear Gd-based agents. 'The ACR continues to endorse the need for additional research efforts directed towards greater understanding of the mechanisms, cellular effects, and clinical consequences of gadolinium tissue deposition. At this time, there is no compelling evidence that any GBCAs, including linear ones, pose any safety risk with respect to brain deposition of gadolinium. Further, linear agents have significant and well-documented diagnostic utility, and in some instances may have more desirable pharmacologic properties or a lower acute reaction risk than macrocyclic agents.'

More: https://www.imageanalysis.org.uk/general/mri-gadolinium

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On the 10th March, EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended the suspension of the marketing authorizations for four linear gadolinium contrast agents because of evidence that small amounts of the gadolinium they contain are deposited in the brain. There are no signs of harm to the patient health.

This recommendation provoked a lot of questions and health concerns. It is important to avoid Gd-phobia while ensuring the right attention is given to clinical research patients.

Below is a short review of the therapeutic areas, where contrast agents are used with a brief note of the advantages they bring. This is followed by the review of the liner vs macrocyclic agents with the references to the manufactures’ statements and our assessments. Note that this is an overview of our current work and not a research article.

What is Gd-contrast and why it is used to image patients?

MRI contrast agents are used to improve the visibility of internal body structures on MRI. MRI contrast agents may be administered by injection into the blood stream or orally and used routinely in clinical practice. The human body is mostly water; water molecules contain hydrogen nuclei (protons), when imaged, they will become aligned in a magnetic field of an MRI scanner. MRI contrast agents work by shortening the relaxation time of protons inside tissues, thus allowing better separate of the vascular tissue from less or non-vascular. 

MRI with Gd contrast are acquired over a short time period after the patent received Gd injection. Gd-MRI or Dynamic Contrast Enhanced (DCE)-MRI is a sequence of images of an organ or a tissue capturing how the tissue takes up Gd contrast and then releases it back to blood. In DCE-MRI, radiologists will see how fast the contrast media is absorbed by the tissue and can quantify its speed and volume of absorption. The speed and the volume of absorption is linked and represents the tissue vascularity. The more vascular tissue (tumor, lesion, synovitis, oedema) will absorb the contrast faster and release it faster, whereas the healthy or non-vascular tissue will show no uptake or wash-out.

Gd MRI has gained a role for all indications that could benefit from its high sensitivity, such as detection of multifocal lesions, detection of contralateral carcinoma and in patients with familial disposition.

Gd-MRI of solid tumors has been shown to have a role in monitoring of neoadjuvant chemotherapy and for the evaluation of therapeutic results during the course of therapy. Use of Gd in breast or prostate MRI can improve the determination of the remaining tumour size at the end of therapy in patients with a minor response. Also, DCE-MRI can improve the early assessment of tumour response to therapy and the assessment of residual tumour after the end of therapy. These scans are critically important in the postoperative work-up of cancers.

In brain imaging, CT scanning can detect the tumor, MRI is significantly more sensitive and is recognized as the modality of choice for the examination of a patient with suspected or confirmed glioblastoma multiforme. MRI without the contrast is limited in its ability to determine type and grade of brain tumors, but advanced MRI techniques, such as perfusion weighted imaging provide much more physiologic information. Gd-MRI findings will include internal cystic areas, internal flow voids representing prominent vessels, internal areas of high signal intensity on T1 (hemorrhagic foci), neovascularity, necrotic foci, significant peritumoral vasogenic edema, and significant mass effect.

In musculoskeletal imaging, MRI gives the ability to assess soft tissue inflammation (synovitis) and bone marrow edemas in inflammatory and degenerative joint disease such as rheumatoid arthritis, osteoarthritis and rare disease. In osteoarthritis (OA), Gd is used to phenotype patients into group of the inflamed and non-inflamed OA, as clinical research shows that certain treatments work only for a particular group of patients. DCE-MRI findings in OA have also been linked to the pain scores in OA patients. In rheumatoid arthritis, the assessment to treatment is measured through quantification of synovium. Gd-MRI gives the ability to differentiate acute disease from chronic and therefore to extract accurate and precise measures of patient improvement.

In summary, by looking at the static MR image, a radiologist can see and measure the size or the volume or even some morphology of the tissue (shape, contour, level of pixel intensity). Contrast agents enable better visibility, which is very valuable. The second reason for the use of the contrast agents is to capture the dynamic behavior of the tissue as opposed to the static one and therefore make earlier diagnostic or research decisions.

Note, that it is possible to gain information about tissue’ dynamic behavior by looking at other sequences such as STIR, DWI or combination imaging – PET+MRI or PET+CT. These types of imaging can aid the diagnostic and clinical research decisions but will require amendment of clinical and research protocols, which are currently relying on the use of the contrast media as well as further validation of these sequences vs the gold standard.  

Does contrast cause harm to the patient?

During a clinical MRI examination, a patient will not receive radiation that is capable of damaging or altering the chemical structure of DNA. No symptoms or diseases linked to gadolinium in the brain have been reported so far. Deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin plaques and nephrogenic systemic fibrosis, a scarring condition in patients with kidney impairment. Prior to administration of contrast agent the patient will undergo thorough clinical assessment to ensure no kidney impairment.

Linear vs macrocyclic contrast agents and their manufactures

There are 2 structurally distinct categories of commercially available contrast agents: linear (“open chain”) or macrocyclic. Linear agents have a structure more likely to release gadolinium, which can build up in body tissues. Other agents, known as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium. The research into the contrast agents is being undertaken by major manufactures of contrast and clinicians.

The four agents recommended for suspension are referred to as linear agents.

Some linear agents will remain available: gadoxetic acid, a linear agent used at a low dose for liver scans, can remain on the market as it meets an important diagnostic need in patients with few alternatives. In addition, a formulation of gadopentetic acid injected directly into joints is to remain available because its gadolinium concentration is very low – around 200 times lower than those of intravenous products.

Contrast Manufactures and their Agents:

• Guerbet markets Dotarem? and Artirem? (gadoteric acid), products belonging to the class of macrocyclic gadolinium-based contrast agents: https://www.guerbet.com/fileadmin/user_upload/home/news/2017/Guerbet_Press_Release-March_13_2017_FINAL3.pdf
• Bayer markets Gadavist? (macrocyclic), Eovist? (linear), and Magnevist? (linear), https://www.radiologysolutions.bayer.com/products/mr/contrast/
• Bracco markets ProHance – macrocyclic agent and MultiHancem and Omniscan – linear agents, https://imaging.bracco.com/us-en/products-and-solutions/contrast-media/multihance
• GE healthcare markets OptiMARK, the linear class agent and ClariscanTM , macrocyclic agent https://www.businesswire.com/news/home/20170228005161/en/GE-Healthcare-expands-MRI-contrast-media-product

PRAC recommends that macrocyclic agents be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable.

Examples of Gd-MRI in Clinical Applications 

The first image is an MR image acquired from a patient with breast cancer. On the left is a typical MR image without Gd contrast. Once the Gd is injected, several scans will be acquired in a sequential manner, within a short time, the tissues which ‘react’ to Gd, e.g. tumors or lesions, will become brighter (see the scan 2 and 3). This example illustrates added clarity between the tumor and normal tissue.

Similarly, in the hand of the patient with an inflamed joint (rheumatoid arthritis), we can see much clearer the inflammation and therefore judge the progression of the disease or response to treatment. 

MRI of a patient with osteoarthritis without (left) and with Gd contrast (right) showing inflammation within the knee joint which was previously invisible in the MRI without contrast. Contrast MRI (right) is showing the synovial tissue is reacting to Gd, thus perfused. Gd contrast allows a radiologist to differentiate between the ‘normal’ tissue and inflammation, linking the inflammatory activity to the pain this patient might be experiencing or even to the future joint destruction.

By looking at the behavior of the tissue over time (the time needed to absorb and release the contrast agent by the tissue), a radiologist is analyzing the tissue’s dynamic behavior, the depth or severity of inflammation (inflammatory disease) or the tumor micro-environment (for oncology). This becomes extremely valuable when you can start quantifying the tissues’ dynamic behavior. Such quantification will reveal the difference between necrotic and active tissue, which is not visible in static MR images. To make this example more real, below is an Gd-MR image of glioma processed with pixel-by-pixel algorithm (Dynamika) and you can clearly see that the part of the tumor is necrotic (no color, indicating no reaction to the contrast agent), whereas the tumor itself if not a homogeneous growth but highly dynamic vascular structure with certain part more vascular than the others.

In musculoskeletal images of patients with fractures and oedema, quantification of Gd-MRI helps understanding if the blood supply was cut, causing discomfort to patients and make a yes / no decision to the surgery. In the knee image, with Gd, we can assess the presence of bone marrow edema and make diagnostic and treatment decisions based on the severity of bone inflammation. 

MRI of breast cancer patient with a solid tumor. MRI image with contrast has been proceed with Dynamika to show that within the tumor some tissue is much more vascular than the others, thus enabling more precise quantification of the tumor volume and tissue vascularity.  

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