Preliminary study of Gd-EOB-DTPA contrast-enhanced magnetic resonance imaging for determining gross tumor volume in hepatocellular carcinoma radiotherapy

Purpose: The aim of this study was to evaluate the feasibility of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast-enhanced magnetic resonance imaging (CE-MRI) for determining the gross tumor volume (GTV) of hepatocellular carcinoma (HCC).

Methods: A retrospective analysis was conducted on 12 patients diagnosed with HCC (18 lesions) who received radiotherapy and underwent magnetic resonance (MR) simulation. Six series images, including MR T₁-weighted image (T₁WI) and contrast-enhanced T₁WI (CE-T₁WI) at 15 s, 45 s, 75 s, 150 s, and >20 min after Gd-EOB-DTPA injection, were obtained, and the GTV was determined in the different temporal images. The differences in mean signal intensity (SI), SI contrast between the HCC and liver tissue, volume and shape of HCC GTV among different phases were compared.

Results: (1) The mean SI of liver tissue reached its peak enhancement at >20 min, showing a 140.90 ± 64.69% increase, compared with T₁WI (p < 0.05). (2) Compared with CE-T₁WI_-20min, the mean SI of the HCC increased by -41.19~18.09% from T₁WI, CE-T₁WI_-15s to CE-T₁WI_-150s. Conversely, the mean SI of liver tissue decreased by 5.27~55.87% over the same period. Consequently, the SI contrast between HCC and liver tissue decreased by 53.30~89.37%. (3) The maximum GTV volume determined by CE-T₁WI_-20min was (22.80 ± 18.57) cm³, coinciding with the highest value of SI contrast (0.29 ± 0.16). (4) Compared with GTV_-20min, GTV_-T1WI and GTV_-15s~GTV_-150s had volume reductions of 6.73~19.35%. (5) Compared with GTV_-20min, the Dice similarity coefficients (DSC) of GTV_-T1WI and GTV_-15s~GTV_-150s ranged from 0.745 to 0.819. Additionally, the shape change trend of GTV in the CE-T₁WI images was generally consistent with the volume change trend.

Conclusion: CE-T₁WI MR images acquired more than 20 min post-injection of Gd-EOB-DTPA exhibited significant advantages in determining the GTV boundaries and enhancing the contrast of SI between HCC and liver tissue. The CE-T₁WI_-20min sequence is recommended for determining HCC GTV.

Introduction

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and ranks fourth among the causes of tumor-related deaths (1). The 5-year survival rate for patients with HCC is less than 20% (2). Precision radiotherapy has become indispensable for the comprehensive treatment of HCC, significantly improving the efficacy of radiotherapy while reducing the incidence of radiation-induced liver disease (RILD) (1). Notably, accurate determination of gross tumor volume (GTV) is essential to ensure the accuracy and efficacy of radiotherapy for HCC (3).

With a high soft-tissue resolution, magnetic resonance imaging (MRI) offers a clear determination of the HCC boundaries (4). Extracellular agents (ECAs) are commonly used in clinical practice for contrast-enhanced magnetic resonance imaging (CE-MRI) of HCC due to their capability to achieve a high contrast between the tumor and liver tissue in the arterial phase, which is useful when detecting HCC. However, the contrast is reduced in the delayed phase, which poses challenges for GTV determination (5). Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a hepatobiliary-specific MR contrast agent that combines the characteristics of ECAs with those of hepatobiliary-specific contrast agents (6). Notably, hepatobiliary phase imaging showcases heightened liver tumor contrast and clear tumor boundaries (6).

However, few reports have explored the determination of HCC GTV using Gd-EOB-DTPA CE-MRI, which highlights the need for in-depth feasibility studies. Therefore, this study aimed to provide a basis for determining the GTV of HCC based on Gd-EOB-DTPA by quantitatively analyzing the differences in HCC imaging using different temporal CE-MRI sequences.

Materials and methods

Patient information

A retrospective study was conducted on 12 patients with HCC (18 lesions) who received radiotherapy at Shandong First Medical University Affiliated Cancer Hospital between January and October 2023. The mean age was 61.17 years (range: 53~77 years). The cohort included nine males (14 lesions) and three females (4 lesions). Detailed information of the patients is shown in Table 1.

Table 1

Table 1. Basic patient information.

The inclusion criteria were listed as follows: (1) confirmation of HCC by pathological biopsy, (2) absence of contraindications to MR, (3) without radiotherapy previously, and (4) availability of MR contrast-enhanced T₁-weighted imaging (CE-T₁WI) enhanced at 15 s, 45 s, 75 s, 150 s, and 20 min post-contrast agent injection. Ethical approval for this study was obtained from the Ethics Review Committee of Shandong Cancer Hospital (Ethics approval number: SDTHEC201903032), and all patients provided signed informed consent.

MR simulation

All patients were fixed in a vacuum-log bag, in a supine position with their arms above their heads, and MR simulation localization was performed on a GE 3.0T superconducting MR scanner (Discovery 750W, GE Healthcare, Chicago, IL, USA). The scanning range was from 3–4 cm above the diaphragm to the lower pole of the right kidney (7). Six sequences of scanning were performed in sequence: the pre-contrast T₁-weighted images (T₁WI) scan and CE-T₁WI scan at 15 s, 45 s, 75 s, 150 s, and >20 min after intravenous injection of Gd-EOB-DTPA (Primovist; Bayer AG, Berlin, Germany). The CE-T₁WI sequences were labeled as CE-T₁WI_-15s, CE-T₁WI_-45s, CE-T₁WI_-75s, CE-T₁WI_-150s, and CE-T₁WI_-20min, respectively. Additionally, the pre-contrast T₁ scan is hereinafter referred to as T₁WI; the scanning process is shown in Figure 1.

Figure 1

Figure 1. MR simulation positioning sequence scanning process. DWI, diffusion-weighted imaging; T₂ FS, T₂-weighted imaging with fat suppression.

The MR scanning sequence parameters were as follows: TR = 5.2 ms, TE = 2.7 ms, FOV = 42~50 cm, matrix = 296 × 256 mm, slice thickness = 3.0 mm, slice spacing= 0 mm, with end-expiration breath holding (EEBH) respiratory state. The CE-T₁WI sequence was administered with an MR injection system (MEDRAD@ Spectris Solaris EP, Bayer, Leverkusen, Germany) at a dose of 0.1 mL/kg and an injection rate of 1 mL/s. Following the Gd-EOB-DTPA injection, a 20 mL flush of normal saline was administered.

HCC GTV determination, naming, and registration

The lesion was defined as a mass with low-to-medium signal intensity (SI) on T₁WI, exhibiting high SI at CE-T₁WI_-15s and relatively low SI from CE-T₁WI_-45s to CE-T₁WI_-20min (Figure 2).

Figure 2

Figure 2. Schematic diagram of MRI images across different phases in a patient with HCC. (A) T₁WI; (B–F) CE-T₁WI acquired at 15 s, 45 s, 75 s, 150 s, and 20 min post-intravenous injection of Gd-EOB-DTPA, respectively.

All MR images were imported into MIM Maestro software (version 7.1.7, Cleveland, OH, USA). The T₁WI sequence images were selected as the primary sequence for registration, and the remaining five imaging sequences were rigidly registered to the T₁WI sequence. A radiation oncologist manually determined the GTV on T₁WI, CE-T₁WI_-15s~CE-T₁WI_-20min sequences. This determination was subsequently reviewed and modified by two additional radiation oncologists. In cases of disagreement, the three doctors discussed and reached a consensus on the GTV boundaries. The GTVs were labeled sequentially as GTV_-T1WI, GTV_-15s, GTV_-45s, GTV_-75s, GTV_-150s, and GTV_-20min. In addition, a 1 cm³ volume of liver tissue, locating 2 cm outside the lesion and avoiding the large hepatic artery, hepatic vein, portal vein, and bile duct system, was designated as liver tissue.

GTV information acquisition

Statistical analysis encompassed the mean SI and SI contrast of the HCC GTV and liver tissue, as well as the volumes of all GTVs. Additionally, comparisons were conducted between the GTV_-20min and other GTVs of Dice similarity coefficient (DSC), volume differences, and volume reduction rates. The SI contrast was calculated using Equation 1, whereas the DSC is defined by Equation 2. Equation 3 was used to determine the rate of volume reduction.

$\begin{array}{ll}SIcontrast=\frac{|S{I}_{HCC}-S{I}_{livertissue}|}{S{I}_{livertissue}}& (1)\end{array}$

$\begin{array}{ll}DSC=\frac{2(|GT{V}_{-x}|\cap |GT{V}_{-20\min }|)}{\left|GT{V}_{-x}\right|+\left|GT{V}_{-20\min }\right|}& (2)\end{array}$

$\begin{array}{ll}volumereductionrate=\frac{GT{V}_{-20\min }-GT{V}_{-x}}{GT{V}_{-20\min }}& (3)\end{array}$

Note: GTV_-x represents a certain sequence of GTV, and SI_HCC represents the HCC SI. SI_{liver tissue} represents liver tissue SI.

Statistical analysis

Statistical analyses were conducted using IBM SPSS statistical software (version 25.0, Armonk, NY, USA). The Wilcoxon test was used to analyze the differences in the mean SI, SI contrast of the GTVs and liver tissue, and GTV volumes. Statistical significance was set at p < 0.05.

Results

Comparison of the mean SI between GTV and liver tissue across different phases

Comparison of the mean SI values of GTVs across different phases

The mean SI of the GTVs exhibited a trend of initially increasing and then gradually decreasing across the different phases. The most significant increase was observed from GTV_-15s to GTV_-45s (Figure 3). Among the different phases, the mean SI of GTV_-45s was the highest (501.01 ± 229.11), whereas GTV_-T1WI exhibited the lowest mean SI at 229.06 ± 68.22 (Table 2).

Figure 3

Figure 3. Trends in the mean SI of liver tissue and HCC GTV and SI contrast across different phases.

Table 2

Table 2. Summary table of mean SI and SI contrast between HCC and liver tissue across different phases.

Compared with GTV_-20min, the mean SI of GTV_-T1WI and GTV_-15s~GTV_-150s exhibited an increase ranging from -41.19% to 18.09% (Table 2). Except for GTV_-150s, there was a significant difference in the mean SI between GTV_-20min and the other GTVs (p < 0.05). Furthermore, in pairwise comparisons of the GTV SI, significant differences were observed for all GTVs, except for GTV_-45s and GTV_-75s (p < 0.05) (Figure 4).

Figure 4

Figure 4. GTV grey histogram of a HCC patient at six phases. (A) T₁WI; (B–F) CE-T₁WI at 15 s, 45 s, 75 s,150 s and 20 min after the intravenous injection of Gd-EOB-DTPA.

Comparison of mean SI of liver tissue across different phases

The mean SI of the liver tissue exhibited an increasing trend, with the most significant increase observed from CE-T₁WI_-15s to CE-T₁WI_-45s. There was no significant change from CE-T₁WI_-45s to CE-T₁WI_-150s. However, a slight yet significant increase was observed from CE-T₁WI_-150s to CE-T₁WI_-20min (Figure 3). The mean SI of liver tissue reached its maximum at CE-T₁WI_-20min, recorded as 651.64 ± 357.75, and its minimum at T₁WI, with a value of 256.21 ± 88.29 (Table 2). Notably, compared with CE-T₁WI_-20min, the mean SI of liver tissue decreased by 5.27~55.87% on T₁WI and CE-T₁WI_-15s~CE-T₁WI_-150s (Table 2).

The difference in the mean SI between CE-T₁WI_-20min and the other phases was significant (p < 0.05) (Figure 5). In the pairwise comparison of the SI of liver tissue across different phases, the mean SI between the other phases showed significant differences (p < 0.05), except for CE-T₁WI_-45s and CE-T₁WI_-75s; CE-T₁WI_-45s and CE-T₁WI_-150s; and CE-T₁WI_-75s and CE-T₁WI_-150s.

Figure 5

Figure 5. Grey histogram of liver tissue in a HCC patient at six phases. (A) T₁WI; (B–F) CE-T₁WI at 15 s, 45 s, 75 s,150 s and 20 min after the intravenous injection of Gd-EOB-DTPA.

Comparison of SI contrast across different phases

Following the injection of Gd-EOB-DTPA, the SI contrast between HCC and liver tissue increased progressively over time, with the most significant increase observed between CE-T₁WI_-150s and CE-T₁WI_-20min (Figure 3). The SI contrast was highest at CE-T₁WI_-20min, with a value of 0.29 ± 0.16, whereas it was the lowest at CE-T₁WI_-15s, with a value of 0.05 ± 0.19 (Table 2). Additionally, significant differences were observed in the SI contrast between CE-T₁WI_-20min and the other phases (p < 0.05).

Comparison of different GTV volumes

After injection of Gd-EOB-DTPA, the GTV volumes initially decreased and then gradually increased over time. GTV_-20min exhibited the largest volume, with an average of 22.80 ± 18.57 cm³, whereas GTV_-45s demonstrated the smallest volume, averaging 20.08 ± 18.78 cm³ (Figures 6, 7).

Figure 6

Figure 6. Schematic diagram of different GTVs and DSC changes.

Figure 7

Figure 7. Schematic diagram of the volume difference between GTV across different MR phases in comparison to the GTV_-20min of a patient with HCC. (A) T₁WI; (B–E) CE-T₁WI acquired at 15 s, 45 s, 75 s, and 150 s after the intravenous injection of Gd-EOB-DTPA; (F) GTV_-20min volume diagram.

Compared with GTV_-20min, GTV_-T1WI exhibited the smallest volume reduction rate, with an average of 6.73 ± 16.25% (p>0.05). Conversely, GTV_-45s showed the largest volume reduction rate, with an average of 19.35 ± 17.14% (p < 0.05) (Table 3). Statistical analysis revealed significant volume differences between GTV_-20min and GTV_-15s, GTV_-45s, and GTV_-75s (p < 0.05).

Table 3

Table 3. Summary of different GTV volumes, volume differences, and volume reduction rates compared with GTV_-20min.

Comparison of the shapes of different GTVs compared with GTV_-20min

Compared with GTV_-20min, the shape and volume change trends of GTVs were generally consistent. The DSC values for GTV_-T1WI to GTV_-150s were 0.819 ± 0.050, 0.745 ± 0.097, 0.752 ± 0.195, 0.810 ± 0.086, and 0.811 ± 0.083, respectively (Figures 6, 8), with GTV_-T1WI exhibiting the largest DSC and GTV_-15s showing the smallest DSC.

Figure 8

Figure 8. Comparison of GTV shapes across different phases of MR in a patient with HCC. (A) GTV shape determination on T₁WI; (B–F) GTV shape determination at 15 s, 45 s, 75 s, 150 s, and 20 min after the intravenous injection of Gd-EOB-DTPA; (G) Determination display of six temporal phases on T₁WI; (H) Enlarged display of GTV shape determination.

Discussion

Accurate determination of the GTV is crucial for improving the efficacy of HCC radiotherapy (3, 8). Therefore, it is pivotal to precisely display and determine the boundary between the tumor and surrounding liver tissue (3). MRI offers superior soft tissue resolution to CT, making it particularly effective for visualizing tumor boundaries (4). Based on previous studies, imaging performed 45s after ECA injection has demonstrated significant advantages in determining tumor volume and shape (9). However, the application of Gd-EOB-DTPA, a hepatobiliary-specific MR contrast agent, in defining the boundaries of HCC GTV has been scarcely investigated. This study aims to evaluate the impact of Gd-EOB-DTPA CE-MRI at different phases on HCC boundary visualization and to provide a theoretical foundation for selecting the optimal phase for GTV determination using Gd-EOB-DTPA CE-MRI.

The difference in blood supply between HCC and liver tissue serves as the foundation for CE-MRI using Gd-EOB-DTPA. The extent and pattern of enhancement observed between lesions and liver tissue following the injection of Gd-EOB-DTPA typically correlates with factors such as perfusion, diffusion level of contrast agent, and expression of the hepatocyte membrane transport proteins OATP1B1 and OATP1B3 (10–13). Notably, Gd-EOB-DTPA exhibits the characteristics of both an ECA and hepatobiliary-specific contrast agent, making it valuable for imaging applications that require visualization of both the vascular and hepatobiliary phases (14). Specifically, the early stages after the injection of Gd-EOB-DTPA exhibit characteristics typical of ECAs. This phase aids in assessing the blood supply to the lesion. Subsequently, during the hepatobiliary phase, the contrast agent demonstrates hepatobiliary-specific characteristics. This phase reflects the presence or absence of liver function and facilitates the visualization of lesions (6).

In this study, the mean SI of both liver tissue and HCC increased most rapidly from 15 s to 45 s after contrast agent injection, which is consistent with the findings by Hamm et al. (15). The injection of an early contrast agent exhibits the characteristics of ECAs by shortening the tissue T₁ relaxation time (16). At 60 s after injection, hepatocytes begin to absorb Gd-EOB-DTPA, which therefore gradually increases the SI of the liver tissue (6). At 150 s after injection, hepatobiliary-specific contrast agent characteristics start to emerge. As the contrast agent enters the extracellular space from the blood vessels, hepatocytes with normal liver function begin to take up Gd-EOB-DTPA. The SI of the liver tissue, which is influenced by both hepatocytes and the extracellular space contrast agent, increases noticeably (17, 18). Specifically, in HCC, Gd-EOB-DTPA gradually leaves the blood circulation and lacks normal hepatocyte uptake function, leading to a significant decrease in SI (17, 18).

Due to the lower dosage of Gd-EOB-DTPA compared to ECAs, the arterial phase enhancement of HCC was not significant, resulting in a small difference in SI between the tumor and liver tissue, which aligns with the findings of Son et al. (5). As the contrast agent in HCC gradually flows out with the blood, the amount of contrast agent in liver tissue gradually increases. The discrepancy in the SI is heightened between the two tissues, making the boundary between the lesion and liver tissue increasingly distinct. In the present study, the SI contrast was most significantly increased between 150 s and 20 min. Specifically, the SI contrast at 150 s was 37.93% lower than that at 20 min. This was attributed to the contrast agent entering the hepatobiliary phase 20 min after injection, during which the liver tissue re-uptakes Gd-EOB-DTPA (10–12). Consequently, there was a significant increase in SI, compared with the SI at 150 s. However, HCC without hepatocyte function no longer takes up contrast agents, leading to minimal changes in SI (10). Therefore, the contrast between the lesion and surrounding liver tissue was improved, and boundary imaging was clearer at 20 min. This enhancement is beneficial for accurately determining the GTV.

To precisely determine the HCC GTV, it is essential to not only ensure high contrast between the tumor and liver tissue but also to ensure adequate tumor imaging. Due to the dynamic changes in the penetration and outflow of contrast agents, most scholars advocate the use of multi-temporal imaging to fully visualize tumor tissues, consequently enhancing the accuracy of GTV determination (19, 20). However, after understanding the diffusion level of the contrast agent, blood perfusion characteristics, and hepatocyte specificity of Gd-EOB-DTPA, we believe that it is unnecessary to fuse multi-temporal images to determine the GTV based on Gd-EOB-DTPA.

Upon comparing the GTV volumes across different phases, it was observed that the maximum volume was observed on the images acquired 20 min after Gd-EOB-DTPA injection. On the one hand, in HCC, 75% of the blood supply originates from newly generated tumor blood vessels, which possess incomplete and highly permeable basement membranes. Most of the contrast agents have already diffused out of the lesion by 20 min, and the tumor tissue lacking hepatocyte function no longer takes up the contrast agent. On the other hand, the liver tissue has sufficient time to take up the contrast agent and exhibits hepatobiliary phase characteristics. These two mechanisms synergistically resulted in the largest observed GTV.

The volumes of GTV_-15s to GTV_-75s were 15.20~19.35% smaller than GTV_-20min, possibly caused by an imbalance in the penetration and outflow of contrast agents in the HCC, leading to insufficient HCC imaging. The lack of a significant difference in volume and shape between GTV_-T1WI and GTV_-20min may be attributed to the low contrast between the tumor and liver tissue in the absence of the contrast agent. This leads to unclear imaging of the tumor boundary and, consequently, a larger volume. However, due to significant determination errors, its use as the preferred sequence for HCC GTV determination is not recommended.

Based on the CE-T₁WI images, the longer the time after the Gd-EOB-DTPA injection was completed, the smaller the difference in volume and shape between the GTV and GTV_-20min. This demonstrates the significance of contrast agent penetration and outflow in HCC imaging. In addition, a small number of HCCs exhibited hypovascularity, with minimal apparent enhancement in the arterial phase. However, determining HCCs based on 20-min CE-T₁WI images can help decrease the likelihood of missed diagnoses (19, 21).

This study’s innovation lies in utilizing the hepatobiliary-specific contrast agent Gd-EOB-DTPA CE-MRI to determine the HCC GTV. It quantitatively analyzed the differences in HCC GTV determination across different MR phases using Gd-EOB-DTPA, confirming its feasibility in determining HCC GTV for radiotherapy. The primary limitation is the long scanning time required for multiple sequences. To ensure image clarity, high requirements are placed on a patient’s respiratory coordination, resulting in reduced patient tolerance. However, this study excluded images with scanning durations exceeding 20 min. In addition, the small sample size is another limitation of this study. The goal of this study was to verify the feasibility of Gd-EOB-DTPA CE-MRI in determining GTV in radiotherapy. Although the number of subjects was small, the image quality was high. In the future, we will expand the sample size for multi-center promotion.

In summary, when Gd-EOB-DTPA CE-MRI was used to determine the GTV, the CE-T₁WI sequence with a phase >20 min after injection had apparent advantages in displaying the GTV boundaries and differences in SI. Therefore, it is recommended as the scanning sequence for determining the GTV.

Data availability statement

All data obtained during the current study are available from the corresponding author on reasonable request.

Ethics statement

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

KM: Writing – original draft, Data curation, Investigation, Methodology. GG: Supervision, Software, Writing – review & editing. RW: Supervision, Writing – review & editing. YY: Formal Analysis, Funding acquisition, Data curation, Supervision, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was supported by National Nature Science Foundation of China (Grant Nos. 82072094, 82001902, and 12275162) and Nature Science Foundation of Shandong Province (Grant Nos. ZR2020QH198 and ZR2019LZL017).

Acknowledgments

The authors (KNM, GZG, RZW and YY) acknowledge financial support for their research work and contribution writing this paper from their sponsors including National Nature Science Foundation of China (Grant Nos. 82072094, 82001902, and 12275162) and Nature Science Foundation of Shandong Province (Grant Nos. ZR2020QH198 and ZR2019LZL017).

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Abbreviations

HCC, hepatocellular carcinoma; RILD, radiation-induced liver disease; GTV, gross tumor volume; MRI, magnetic resonance imaging; ECAs, extracellular agents; CE-MRI contrast-enhanced magnetic resonance imaging; Gd-EOB-DTPA gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid; CT, computed tomography; T₁WI, T₁-weighted images; DWI, diffusion-weighted imaging; T₂ FS, T₂-weighted imaging with fat suppression; SI, signal intensity; DSC, dice similarity coefficient.

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