In this study, we found that the maximum TTP of brain metastases, primary brain tumors, and meningiomas was approximately 5 min. Qualitative and quantitative assessments of contrast enhancement supported this finding, showing that images acquired 5 and 7 min after contrast agent injection were comparable in terms of lesion conspicuity and enhancement (Fig. 5). Enhancement on images acquired after 7 min was only marginally better for the longest diameter measurement of the lesions.
Our observation of the gradual contrast enhancement in the primary brain tumor and brain metastases until 5 min after contrast agent injection when using DCE imaging partly contradicts a previous study that reported images acquired after 1 min showed an equal contrast effect to the images acquired after 5 min[10]. The researchers also found that images after 1- and 5-min delays showed a higher contrast effect than images acquired after a 10-min delay [10]. Despite our result rejecting the quality of images after 1 min, the gradual enhancement of the lesions until 5 min after contrast injection, and the comparability between images acquired after 5 and 7 min, supports the previous study’s assumption that waiting for five minutes after contrast agent injection was effective for intracerebral metastases detection [10]
Intracranial brain tumors and metastases reportedly revealed persistent or slow gradual enhancement over time [14]. However, recent DCE studies showed that primary brain tumors might exhibit early enhancement and delayed washout, not a plateau [11, 15]. Engelhorn et al. studied DCE features of experimental gliomas and found that waiting eight minutes after contrast agent injection revealed 84% of the tumors and seemed to be a practical clinical compromise between imaging delay time and detection rate [16]. A few DCE imaging studies have dealt with brain metastases [17–19], but none has determined the peak enhancement time. Our study was the first to show that the optimal brain metastases enhancement could be achieved 5 min after contrast injection based on DCE imaging data.
Differences in enhancement characteristics between the three groups might be attributable to the degree of hypervascularity, presence of dural arterial supply, difference in histologic type, and abundance of glycosaminoglycan [20]. The maximum TTP in our study was much longer than the mean TTP of the target lesion, understandable considering that the tumor enhancement curve shows a different pattern depending on the tumor portion [11]. Given tumor heterogeneity, maximum TTP might represent the entire tumor more comprehensively than mean TTP does.
The imaging assessment also confirmed that images acquired after 5 and 7 min were comparable in lesion conspicuity, ER, and CR. Our study is also in line with a previous study [10] that found lesion conspicuity and the quantitative results to become prominent over the first 5 min after contrast injection but not extending to the point of 7 min after contrast injection. However, Yuh et al. reported that small brain metastases were better detected on images acquired after a far longer waiting time (10, 20, and 30 min) [8]. Cohen-Inbar et al. also discovered more lesions 20 min after contrast agent injection, especially in association with the posterior circulation [21]. The mean diameter of the observed lesions was approximately 3 mm. Accordingly, a recent study recommended waiting 10-15 min before acquiring images to detect brain metastases [22].
However, higher sensitivity for brain metastases by any method could be at the risk of a higher false-positive rate, as when using a higher GDCA dose [23]. Besides brain metastases, solid enhancing nodules can be observed in various diseases, including vasculitis, demyelinating plaques, and infections [24]. Non-tumorous lesions with blood-brain barrier leakage can particularly benefit from delayed images, unlike brain metastases or primary brain tumors that inherently have pathological hypervascularity[25].
Our diameter measurement also revealed that waiting 5 or 7 min did not affect the measurement power of the tumor dimensions. Brain metastases response assessment is important but was not standardized until the response assessment in neuro-oncology brain metastases (RANO-BM) criteria were recently introduced [26]. Measurable disease is defined in RANO-BM as a contrast-enhancing lesion that can be measured in at least two plane dimensions, with a minimum size of 10 mm. At least a 30% decrease in the sum longest diameter of a CNS target lesion was defined as a partial response while a 20% or more increase in the sum longest diameter of a CNS target lesion was defined as progressive disease [26]. Thus, it is of paramount importance to measure accurately the tumor largest and perpendicular diameters in contrast-enhanced images. Our findings suggest that the appropriate cutoff for the waiting time from injection would be five minutes.
Our results have a potential implication in the era of AI-assisted radiology. The observations in our study could be used as a reference to develop AI-assisted diagnostic tool that deals with heterogeneously obtained imaging data. Second, our result can be used to optimize MRI protocol for quality of patient care and for throughput in MRI. In research hospitals, various sequences could be inserted between contrast agent injection and the contrast-enhanced image acquisition 5 min later. These could include dynamic susceptibility contrast (DSC), DCE, contrast-enhanced FLAIR, and more. In more rural settings, a standard enhanced FLAIR for leptomeningeal pathology could be inserted during the 5 min waiting time. Above all, accurate knowledge of the optimal waiting time could help to improve the patient’s comfort level by reducing the MRI examination time.
Our study has some limitations. First, although we evaluated the entire DCE time-intensity curve for seven minutes, one could argue that estimating the time-intensity curve is inadequate. However, given the tumor pathological innate vascularity, our findings could reasonably represent the nature of the tumorous conditions studied. Second, several factors might affect the contrast enhancement, including MRI sequence parameters, post-processing software programs, and contrast agents. We acknowledge that different contrast agents, such as the macrocyclic ionic agent, might show different results. Nevertheless, given the binding nature of the macrocyclic ionic agent to glycosaminoglycan within the tumor, we assume that such a GDCA might accentuate our results rather than disapprove them [27]. This recent paper found no difference in DCE parameters between gadobutrol and gadoterate dimeglumin [27].