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Could an emerging modality provide a viable alternative to gadolinium-based contrast agents (GBCAs) in this high-risk patient population?
Conducting magnetic resonance imaging (MRI) with a contrast agent is a sensitive and useful imaging method to assess and select patients eligible for metastatic resection, or locally directed non-surgical treatment. One may also utilize MRI contrast agents to help determine the efficacy of a given treatment and/or for surveillance of possible disease recurrence.
However, MRI with contrast agent is not suitable for all patients. Those with severely impaired renal function are at risk of complications from the contrast agents that are currently available on the market. Accordingly, let us take a closer look at the current landscape for contrast agents for the imaging of patients with liver metastasis and severe kidney impairment.
Cancer can be a difficult disease to diagnose and treat because of its ability to metastasize beyond the location of the primary tumor. While cancer can spread anywhere in the body, certain areas, like the liver, are more prone to metastases than others. In fact, the liver is the second most common organ for metastases (after the lymph nodes) and liver metastases reportedly play a significant role in mortality rates for patients with breast or colorectal cancer.
Magnetic resonance imaging is considered the preferred imaging modality for both initial cancer disease staging and monitoring of liver metastases. The use of contrast agents is key to improving the quality of the obtained MRI scan.
In a recent market research survey conducted by Ascelia Pharma, 270 health-care professionals (HCPs) in the United States (ranging from radiologists and oncologists to nephrologists and pharmacists) provided detailed insights into decision making on imaging and the use of contrast agents for those with severely reduced kidney function. This research found that almost half (48 percent) of abdominal MRIs performed by radiologists are for patients with liver cancer or metastases.
Most of the currently available contrast agents are based on gadolinium, a heavy metal, which, when used on patients with impaired kidney function, can increase the risk of nephrogenic systemic fibrosis (NSF). This is a rare but serious and life-threatening condition, which causes extensive thickening and hardening of the skin. Nephrogenic systemic fibrosis can lead to joint contractures as well as fibrosis of inner organs, which can result in severe immobility or death.
Current contrast agents carry black box warnings from the Food and Drug Administration (FDA) for patients with severely impaired kidneys. Other regulatory agencies, including the European Medicines Agency (EMA), have published guidelines for the use of gadolinium-based contrast agents (GBCAs) in MRI with restrictions on their use for patients with severely reduced kidney function. Accordingly, when it comes to MRI use for patients with severe kidney impairment, contrast enhancement is not recommended, which reduces image quality and the ability to detect and localize cancer tumors or metastases.
However, a serious consequence of this suboptimal diagnostic procedure is the impact it may have on timely diagnosis and/or treatment accuracy (surgery or drug therapy), and therefore a patient’s chances of survival. This presents a real challenge for health-care professionals: how does one perform imaging scans on these patients effectively without potentially inducing harm with the currently available contrast agents?
Assessing Current Trade-Offs with Image Quality and Safety of GBCAs
More than 15 percent of the respondents surveyed by Ascelia Pharma said that they have experienced a case of GBCA-induced NSF, and more than half of these health-care professionals have less than 15 years in clinical practice. Ninety percent of HCPs surveyed said they are concerned by issues relating to GBCAs (including NSF), and that patients are generally aware of the risks associated with GBCAs, particularly patients with poor kidney function.
In line with this concern, around 70 percent of the survey respondents prefer to use MRI without a contrast agent and up to 15 percent would use a partial dose of a GBCA when performing an imaging procedure on patients with severe kidney impairment (glomerular filtration rate (GFR) below 30) or acute kidney injury.
The practice of using a partial dose of a GBCA underlines the importance of using a contrast agent to improve image quality and the need to carefully consider the trade-off between image quality and safety for this vulnerable patient population.
A Closer Look at Orviglance
Orviglance (manganese chloride tetrahydrate) is a novel oral contrast agent for MRI. This agent was developed to improve the detection and visualization of focal liver lesions (including liver metastases and primary tumours) in patients with severely reduced kidney function, who are at risk of serious side effects from the currently available class of GBCAs. Orviglance (formerly Mangoral) has been granted an orphan drug designation by the FDA and is currently in phase 3 development.
Orviglance (Ascelia Pharma) has facilitated high quality imaging in comparison to un-enhanced MRI in phase 2 studies. It is based on the chemical element manganese, which is a natural trace element in the body. Orviglance also contains an amino acid and a fat-soluble vitamin to increase the absorption of manganese from the small intestine into the portal liver vein. The manganese is subsequently transported to the liver where it is taken up by hepatocytes without any uptake by cancer cells. The excretion of the agent is biliary and there is minimal systemic exposure.
Pending FDA approval in the future, Orviglance may emerge as a standard of care liver MRI contrast agent for patients with severely impaired kidney function, and possibly help improve outcomes for many patients for whom suboptimal diagnostic options are current clinical practice.
As there is currently no safe alternative for severely renal impaired patients who require an MRI scan of the liver, it is clear that there is a large unmet medical need to be addressed. Preliminary clinical data suggests that Orviglance-enhanced MRI can lead to earlier detection of metastases and detection of smaller metastases compared to non-enhanced MR imaging. This should improve the possibilities of optimal management of liver cancer or metastases, positively impact the quality of life of for patients with these conditions, and possibly lead to higher survival rates.
Mr. Bjartmar is the chief medical officer at Ascelia Pharma. He previously served as the chief medical officer for the Swedish biotech company Wilson Therapeutics and has held senior positions at Lundbeck, Sanofi and Genzyme.