Reducing Gadolinium Exposure in Patients Undergoing Monitoring for Meningiomas

Background Due to the non-malignant and slow-growing nature of many meningiomas, surveillance with serial magnetic resonance imaging (MRI) serves as an acceptable management plan. However, repeated imaging with gold-standard contrast-based studies may lead to contrast-associated adverse effects. Non-gadolinium T2 sequences may serve as a suitable alternative without the risk of adverse effects of contrast. Thus, this study sought to investigate the agreement between post-contrast T1 and non-gadolinium T2 MRI sequences in the measurement of meningioma growth. Methodology The Virginia Commonwealth University School of Medicine (VCU SOM) brain tumor database was used to create a cohort of meningioma patients and determine the number of patients who had T1 post-contrast imaging accompanied by readily measurable imaging from either T2 fast spin echo (FSE) or T2 fluid-attenuated inversion recovery (FLAIR) sequences. Measurements of the largest axial and perpendicular diameters of each tumor were conducted by two independent observers using T1 post-contrast, T2 FSE, and T2 FLAIR imaging series. Lin’s concordance correlation coefficient (CCC) was calculated to assess inter-rater reliability between observers and agreement between measurements of tumor diameter among the different imaging sequences. Results In total, 33 patients (average age = 72.1 ± 12.9 years, 90% female) with meningiomas were extracted from our database, with 22 (66.7%) undergoing T1 post-contrast imaging accompanied with readily measurable imaging from T2 FSE and/or T2 FLAIR sequences. The inter-rater reliability between the measurements of T1 axial and perpendicular diameters was 0.96 (95% confidence interval (CI) = 0.92-0.98) and 0.92 (95% CI = 0.83-0.97), respectively. The inter-rater reliability between the measurements of T2 axial perpendicular diameters was 0.93 (95% = CI 0.92-0.97) and 0.89 (95% CI = 0.74-0.95), respectively. The agreements between the measurement of T1 and T2 FSE axial diameter by each observer were 0.97 (95% CI = 0.93-0.98) and 0.92 (95% CI = 0.81-0.97). The agreements between the measurements of T1 and T2 FSE perpendicular diameter measurements by each observer were 0.98 (95% CI = 0.95-0.99) and 0.88 (95% CI = 0.73-0.95). Conclusions Two-thirds of our patients had meningiomas that were readily measurable on either T2 FSE or T2 FLAIR sequences. Additionally, there was excellent inter-rater reliability between the observers in our study as well as an agreement between individual measurements of T1 post-contrast and T2 FSE tumor diameters. These findings suggest that T2 FSE may serve as a safe and similarly effective surveillance method for the long-term management of meningioma patients.


Introduction
Meningiomas are the most common primary intracranial tumor with incidence rates of 8.6 per 100,000 persons [1]. Due to their non-malignant and slow-growing nature, surgical intervention is not always a necessity, and surveillance via imaging can be an acceptable management plan for asymptomatic patients [2]. Appropriate time intervals for follow-up are at the discretion of individual physicians [2,3]. Given the potential for long-term follow-up (more than five years) and associated multiple imaging scans with goldstandard T1 post-contrast magnetic resonance imaging (MRI) scans, current practice results in repeated administration of contrast agents [2]. Gadolinium (Gd 3+ ) is the chief ingredient of MRI contrast agents, shortening the relaxation time of T1 imaging to produce images that display tissues with greater contrast than those without [4,5]. Following approval of the Food and Drug Administration (FDA) in 1988, gadolinium-based contrast agents (GBCAs) have been widely used for complex clinical diagnosis and are considered extremely safe, with adverse lifethreatening reactions occurring at rates of 0.001-0.01% [6].
GBCAs are categorized into linear and macrocyclic subgroups, corresponding to their chelation and structure. Linear agents have been found to be relatively less stable than their counterparts, releasing free Gd 3+ [4]. In vivo, free Gd 3+ is highly toxic and can be distributed into adjacent tissues such as the bone, lymph nodes, and liver [4]. Adverse consequences of repeated Gd 3+ exposure were first reported in a 2006 study which demonstrated that, in patients with impaired renal function, linear GBCAs may contribute to nephrogenic systemic fibrosis (NSF), characterized by the thickening and hardening of the skin at the distal extremities. Subsequently, it has been recommended to use the macrocyclic iteration and limit repeated exposure; however, no limitations have been placed on patients with normal renal function [1,[7][8][9]. In 2014, Kanda and colleagues published the first study which demonstrated Gd 3+ deposition into brain tissue, specifically with hyperintensity in the dentate nucleus and globus pallidus. These patients had a history of linear GBCA administration but were without renal impairment [10]. Further studies have been conducted with respect to Gd 3+ deposition into brain tissue but adverse sequelae from Gd 3+ deposition have not been demonstrated [11].
Although the adverse effects of long-term contrast exposure are rare and their effects on the brain are currently inconclusive, the potential compromise of patient safety warrants novel strategies. In many cases at our institution, previously identified meningiomas have been adequately measured with T2 sequences, suggesting that these patients could potentially forgo the use of repeated gadolinium exposure. Therefore, we set out to determine the percentage of meningioma patients who have been monitored with T2 imaging at our institution as well as compare the extent of agreement of tumor measurements between T1 postcontrast and T2 non-contrast sequences.

Study overview
Meningioma patients were extracted from the Virginia Commonwealth University School of Medicine (VCU SOM) brain tumor database, which comprises patients presenting for brain tumors between the years 2005-2015. To create a random sample, patients were placed in alphabetical order using their last name, and every other patient was selected. Spinal meningiomas were excluded from this study. The VCU institutional review board approved our proposal and classified this study as a pilot study as, at the time of approval, we were, to our knowledge, the first to investigate the agreement between measurements of T1 post-contrast and T2 non-contrast meningioma diameters. Thus, we determined, without calculation, that a sample size of roughly 30 patients would be both feasible for our observers and adequate for statistical significance.

Tumor measurement
The Response Evaluation Criteria in Solid Tumors (RECIST) was introduced in 2000 and subsequently updated in 2009. Since its introduction and adoption by the oncological community, RECIST has been widely used to report changes in tumor size [12,13]. Still, the simplified ellipsoid volume (ABC/2) has repeatedly demonstrated adequate correlation with planimetric techniques [14,15]. The measurement techniques employed by the raters are a derivation of the latter.
Two measurements were taken on each meningioma by two independent observers (or raters), authors Kristen Johnson (KJ) and Srikar N. Sattiraju (SNS), on each axial T1 post-contrast, axial T2 fast spin echo (FSE), and axial T2 fluid-attenuated inversion recovery (FLAIR) image. The first measurement, the longest dimension, was measured and labeled A. The second measurement, B, was the longest perpendicular dimension to A (Figure 1). Both KJ and SNS were trained by the senior author, an experienced surgical neurooncologist, on how to appropriately conduct these measurements using conventional imaging software (Philips IntelliSpace Radiology).

Statistical analysis
Demographic and tumor variables including sex, location of the tumor, and patient age at imaging were summarized using means and standard deviations or frequencies and percentages. Lin's concordance correlation coefficients (CCC) with 95% confidence intervals (CIs) were calculated to assess inter-rater reliability and tumor diameter measurement agreement [16]. Inter-rater reliability, expressed using CCC, was calculated to determine the agreement in the raters' tumor diameter measurements. Bland-Altman analyses were performed to further illustrate the agreement between inter-rater reliability and tumor diameter measurements [17]. CCC and Bland-Altman statistical analyses were conducted using R Statistical Software (Version 3.6.1, Vienna, Austria). In line with the suggested guidelines, CCC values <0.50 were considered to indicate poor inter-rater reliability or agreement, 0.50-0.75 values were moderate, 0.75-0.90 values were good, and >0.90 values were excellent [18].

Patient demographics
A total of 739 patients were diagnosed with meningioma at VCU between 2005 and 2015, and 33 of these patients were extracted for this study. The mean age of our patient sample at initial MRI imaging was 72.1 ± 12.9 years, ranging from 49 to 92 years with a median of 75 years. There were 30 (90%) females and three (10%) males. There were 10 (30.3%) patients with meningiomas located in the frontal fossa, the most frequently occurring tumor location within our sample, followed by four (12.1%) sphenoid wing meningiomas. This demographic information is summarized in Table 1.      Figure 3.

Discussion
In the present study, there was good and excellent inter-rater reliability between the measurements of meningioma diameters using T1 post-contrast, T2 FSE, and T2 FLAIR images by two similarly trained observers, as indicated by concordance correlation values between 0.75-0.90 and >0.90, respectively, for each type of imaging technique. These findings indicate that the measurements of meningioma diameter obtained from T1 post-contrast, T2 FSE, and T2 FLAIR by these observers are precise and that comparisons of each observer's measurements between imaging techniques are reflective of the accuracy of the instrument used to measure them. Additionally, a similar study found that two neuroradiologists with 20 years difference in imaging reading were able to maintain moderate agreement between meningioma volume (κ = 0.45), which improved to substantial for meningiomas >1 mL (κ = 0.77), suggesting that even less experienced observers can still make accurate measurements [19]. Because these prerequisite findings demonstrated adequate reliability of our observers and the instruments of measure, subsequent analysis of the agreement between meningioma diameter measurements between imaging techniques was appropriate.
In the present study, there was excellent or near-excellent agreement between both observers' measurements of axial and perpendicular meningioma diameters when comparing T1 post-contrast and T2 FSE images of individual tumors. These findings are in line with several recent studies comparing the efficacy of T1 and T2 imaging techniques for measuring meningioma growth patterns. For instance, He et al. (2020) found that measurements of the change in tumor size over time for both T2 and T2 FLAIR imaging techniques were significantly correlated with T1+ contrast imaging of 18 asymptomatic meningiomas [20]. Similarly, T2-weighted imaging was able to accurately measure the size and detect changes in meningioma volume with similar efficacy as T1 post-contrast images, especially tumors >1 mL and those located in the posterior fossa [19,21]. Finally, a recent study by Boto and colleagues found excellent agreement, as measured by intraclass correlation coefficients, between various measurements of meningioma size and growth between T1 three-dimensional gadolinium and two-dimensional T2-weighted imaging [22]. Taken together, these findings bolster the evidence that T2 MRI techniques may be similarly efficacious in measuring meningioma size and growth. Unlike the findings presented in the latter three recent reports, we found that only two-thirds of the meningiomas in our cohort could be measured and followed without the administration of gadolinium-based agents. The common factor of the meningiomas that could not be measured accurately in our study was the lack of intensity of the tumors on T2 imaging. Meningiomas of various sizes or locations were able to be measured accurately with T2 imaging by our raters, and thus the limitation of T2 imaging in our study appears to be associated with the MRI characteristics of the tumors themselves as opposed to their location and size.
The fact that the majority of meningiomas can be measured with non-contrast imaging, along with the similar agreement between T1 and T2 measurements of meningioma tumor size and growth in the present study and prior studies could have significant implications for meningioma surveillance. Namely, they provide substantial evidence that a conversion from gold-standard contrast imaging to non-contrast imaging could avoid contrast-related toxicities without sacrificing efficacy in select patients [19][20][21][22]. Utilizing non-contrast scans more frequently may also be more cost-effective for patients and the healthcare system [22,23].
Despite these findings, gadolinium-based MRI should remain a critical tool in the management of certain meningioma patients given the superior efficacy of contrast in visualizing various aspects of meningioma growth relative to T2 imaging, including those of smaller volume (i.e., <1 mL), en plaque meningiomas, and those with enhancing dural tails [19,24,25]. Indeed, current European Association of Neuro-Oncology (EANO) guidelines recommend a wait-and-see approach for patients with normal life expectancy who have small (i.e., <3 cm) and/or asymptomatic tumors where contrast imaging is used six months after diagnosis, annually for five years, and then biannually [2]. Our findings reported here suggest that routine imaging with non-contrast MR may serve as a means of providing surveillance for the majority of patients without excessive exposure to gadolinium. We note that about one-third of patients have tumors that cannot be visualized well without contrast. These patients will require post-contrast studies for surveillance imaging. Similarly, following complete resection of meningiomas, contrast will be required to identify small nodules of tumor recurrence.

Limitations
There are several limitations associated with the present study. As the data were collected retrospectively, future research could include prospective or randomized studies of patients who have meningiomas capable of being measured on T2 sequences. Another limitation is our small sample size which may affect generalizability. Multi-institution designs in future studies could help alleviate this limitation. Lastly, the measurements were taken by two observers who were not trained physicians and lacked a formal background in neuroradiology. While future studies may consider using observers with formal neuroradiology training, we believe the findings from this study are important as they show that even informally trained observers can acquire specific neuroradiological diagnostic skills.