Optimization of temporal phase in multi-phase contrast-enhanced MRI for gross tumor volume determination in pancreatic cancer radiotherapy

Introduction

Pancreatic cancer is one of the most common malignant tumors with a poor prognosis and a 5-year survival rate of only 10% (1-5). However, 80–85% of patients with pancreatic cancer are diagnosed at an advanced stage, making them ineligible for surgery (6-8). Radiotherapy can improve the local control rate, prolong survival time, and improve the quality of life of patients with locally advanced pancreatic cancer (9,10). A key to successful radiotherapy is the accurate determination of the gross tumor volume (GTV).

The most commonly used imaging method for pancreatic cancer is multi-phase contrast-enhanced computed tomography (CE-CT), which offers high spatial resolution, low cost, and good repeatability (11,12). However, the limited soft-tissue contrast of CE-CT makes it difficult to distinguish tumor boundaries from surrounding inflammation and edema. This uncertainty often leads to imprecise GTV determination. In contrast, magnetic resonance imaging (MRI) offers superior soft-tissue resolution, which compensates for the limitations of CT and facilitates the identification of small or isodense lesions (13,14). Notably, Hall et al. (15) demonstrated that MRI-based GTV determination yields smaller and more precise volumes compared with CT, thereby allowing for better sparing of organs at risk (OARs).

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a crucial method for imaging pancreatic cancers; it reflects the dynamic changes in contrast agents within the tumor and demonstrates the tumor’s blood supply, aiding in the imaging of the tumor tissue (16). Currently, the consensus in radiology studies considers 35–50 s after contrast agent injection to be the peak enhancement period of pancreatic parenchyma, which is beneficial for detecting pancreatic cancer lesions. However, whether this period is suitable for radiotherapy determination remains controversial. Radiotherapy requires clear visualization of the boundary between the tumor and surrounding normal pancreatic tissue, in addition to detecting the tumor lesion. Whether multi-phase enhancement, such as the early arterial phase (15 s), can improve the accuracy of pancreatic cancer boundary determination is still inconclusive. Therefore, this study quantitatively analyzed the differences in signal intensity (SI), volume, and shape of pancreatic cancer in different phases of CE-MRI, providing a basis for optimizing the selection of phases for pancreatic cancer GTV determination. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2163/rc).

Methods

Patient information

A retrospective analysis was conducted on 30 patients with unresectable pancreatic cancer (for palliative purposes) who underwent radiotherapy for the first time at the Affiliated Cancer Hospital of Shandong First Medical University between August 2019 and November 2023. The mean patient age was 61.1 years (35–81 years). The cohort included 21 males and 9 females. Among them, 15 (50%) had tumors located in the head and neck of the pancreas, whereas the remaining patients presented with tumors in the body and tail, as shown in Table 1.

The inclusion criteria were as follows: (I) pancreatic cancer confirmed by pathological biopsy; (II) patients with unresectable advanced pancreatic cancer; (III) first-time radiotherapy; and (IV) magnetic resonance (MR) T₁-weighted images (T₁WI) enhanced images obtained at 15 s, 45 s, 75 s, 150 s, and >20 min after contrast injection. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study is a retrospective image data analysis, with all data anonymized, and does not involve experiments directly applied to humans, so informed consent is not required from patients.

Simulation

CT simulation

All patients were placed in the supine position with their arms above their heads using a vacuum bag. A Philips Brilliance Big Bore CT locator (Philips, Amsterdam, Netherlands) was used for four-dimensional (4D)-CT simulation in a free-breathing state (17). The scanning range included the entire upper abdominal region.

MR simulation

After CT simulation positioning, the patient was placed in the same position and fixed in a GE 3.0T superconducting MR scanner (Discovery 750W; GE Healthcare, Chicago, IL, USA) for MR simulation. Six sequence scans were performed, including T₁-weighted images (T₁WI) and contrast-enhanced T₁-weighted images (CE-T₁WI) at 15 s, 45 s, 75 s, 150 s, and >20 min after the intravenous injection of a paramagnetic contrast agent [gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)]. The CE-T₁WI sequences were named as follows: CE-T₁WI_{-15 s}, CE-T₁WI_{-45 s}, CE-T₁WI_{-75 s}, CE-T₁WI_{-150 s}, and CE-T₁WI_{-20 min}, and the T₁ plain scans were referred to as T₁WI.

The MR scanning sequence parameters were as follows: repetition time (TR) =5.2 ms, echo time (TE) =2.7 ms, field of view (FOV) = 42–50 cm, matrix = 296 mm × 256 mm, slice thickness =3.0 mm, and slice spacing =0 mm. The respiratory state was end-expiration breath holding (EEBH). An MR injection system (MEDRAD^® Spectris Solaris EP, Bayer, Leverkusen, Germany) was used to inject Gd-DTPA at a dose of 0.2 mL/kg with 20 mL of normal saline at an injection rate of 2 mL/s.

Registration, determination, and naming of pancreatic cancer lesions

Lesions were characterized as masses exhibiting low or isointense signal on T₁WI, low signal on CE-T₁WI_{-15 s}, low or equal signal on CE-T₁WI_{-45 s} and CE-T₁WI_{-75 s}, and equal or slightly higher signal on CE-T₁WI_{-150 s} and CE-T₁WI_{-20 min}, as shown in Figure 1.

Figure 1 Schematic of imaging manifestations of pancreatic cancer lesions (arrows). (A) T₁WI; (B-F) CE-T₁WI_{-15 s}, CE-T₁WI_{-45 s}, CE-T₁WI_{-75 s}, CE-T₁WI_{-150 s}, and CE-T₁WI_{-20 min} after the intravenous injection of Gd-DTPA. CE-T₁WI, contrast-enhanced T₁-weighted image; Gd-DTPA, gadolinium diethylenetriaminepentaacetic acid; GTV, gross tumor volume; T₁WI, T₁-weighted images.

All MRIs were imported into MIM Maestro software (version 7.1.7, Cleveland, OH, USA) with T₁WI selected as the primary sequence for registration. The remaining five sequences were rigidly registered in the T₁WI sequence. A radiation oncologist manually determined the GTV on the T₁WI, CE-T₁WI_{-15 s}…CE-T₁WI_{-20 min} sequences. Two other radiation oncologists reviewed and modified the data as necessary. When the three doctors disagreed, they discussed the determination of the range of GTV, among which the GTV was marked as GTV_-T1WI, GTV_{-15 s}, GTV_{-45 s}, GTV_{-75 s}, GTV_{-150 s}, and GTV_{-20 min}.

Additionally, 1 cm³ of the pancreatic tissue outside the lesion was defined as normal pancreatic tissue. Blood vessels and pancreatic ducts were avoided when determining normal pancreatic tissue, and the mean of the three measurements was used as the SI of the normal pancreatic tissue.

GTV information acquisition

The mean SI and SI contrast of the GTV and normal pancreatic tissue, volume of all GTVs, volume difference, volume reduction rate, Dice similarity coefficient (DSC), and Hausdorff distance (HD) compared with GTV_{-15 s} were statistically analyzed.

The SI contrast is expressed in Eq. [1], the volume reduction rate in Eq. [2], the DSC definition in Eq. [3], and the HD definition in Eq. [4].

SIContrast=|SIGTV−SINormalPancreaticTissue|SINormalPancreaticTissue[1]

Volumereductionrate=GTV−15s−GTV−xGTV−15s[2]

DSC=2(|GTV−x|∩|GTV−15s|)|GTV−x|+|GTV−15s|[3]

Note: GTV_-x represents a certain GTV phase. SI_GTV represents GTV SI, and SI_{normal pancreatic tissue} represents normal pancreatic tissue SI.

H(A,B)=max(max︸a∈A{min︸b∈B‖a−b‖,max︸b∈B{min︸a∈A‖b−a‖)[4]

Note: HD is a measure of the similarity between two sets of points. It is a definition of the distance between two sets of points: Assuming there are two sets of points A= {a₁, …, a_p}, B= {b₁, …, b_q}, then the HD between these two sets of points is defined as Eq. [4]. The unit of HD is millimeter (mm). The higher the HD, the greater the difference.

Statistical analysis

All data were analyzed using IBM SPSS statistical software (version 25.0, Armonk, NY, USA), with the measured data expressed as means ± standard deviation. The mean SI, SI contrast of the GTV and normal pancreatic tissue, and GTV were analyzed using the Wilcoxon test, and P<0.05 indicated statistically significant differences.

Results

Comparison of mean SI between GTV and normal pancreatic tissue at different phases

Comparison of mean SI of GTV at different phases

The mean SI of GTV_-T1WI to GTV_{-20 min} ranged from 263.14 to 827.12, as shown in Table 2. The most significant increase in the mean SI occurred between 15 s and 45 s after the injection of Gd-DTPA, reaching a peak at 150s. After this peak, the mean SI began to decrease (Figure 2).

Figure 2 The change in the trend of mean SI of GTV and normal pancreatic tissue at different phases. CE-T₁WI, contrast-enhanced T₁-weighted images; GTV, gross tumor volume; SI, signal intensity.

The mean SI of GTV_{-15 s} to GTV_{-20 min} increased by 93.94–223.80% compared to GTV_-T1WI. Except for GTV_{-75 s} and GTV_{-150 s}, the differences in SI between the other GTV phases were statistically significant (P<0.05). For more detailed information, please refer to the Table S1.

Comparison of mean SI of normal pancreatic tissue at different phases

The mean SI of normal pancreatic tissue across T₁WI and CE-T₁WI_{-15 s} to CE-T₁WI_{-20 min} ranged from 416.35 to 1,089.22, which was significantly higher than the mean SI of the GTV in the corresponding phases (P<0.05, Table 2). The mean SI of GTV across T₁WI and CE-T₁WI_{-15 s} to CE-T₁WI_{-20 min} was lower than that of normal pancreatic tissue by (34.37±13.04)%, (45.01±9.90)%, (27.08±13.02)%, (22.16±11.86)%, (18.39±12.05)%, and (9.93±12.77)%.

Within 45 s after the Gd-DTPA injection, the mean SI of the normal pancreatic tissue showed a continuous increase. In contrast to the mean SI of the GTV, normal pancreatic tissue experienced its most significant increase within 15 s post-injection, reaching its peak at 45 s. Subsequently, SI gradually decreased, with the most substantial decline occurring between 150 s and 20 min (Figure 2).

The mean SI of normal pancreatic tissue increased by 108.84–181.20% in CE-T₁WI_{-15 s} to CE-T₁WI_{-20 min} compared with T₁WI. Except for CE-T₁WI_{-15 s} and CE-T₁WI_{-150 s}, as well as CE-T₁WI_{-15 s} and CE-T₁WI_{-20 min}, the differences in the mean SI of normal pancreatic tissue in the other phases were statistically significant (P<0.05), see Table S1 for details.

Comparison of the mean SI contrast between normal pancreatic tissue and GTV at different phases

The mean SI contrast between normal pancreatic tissue and the GTV on T₁WI and CE-T₁WI_{-15 s} to CE-T₁WI_{-20 min} ranged from 0.10 to 0.45 (Table 2). The contrast was the highest at 15 s and lowest at 20 min, as shown in Figure 3.

Figure 3 The change in the trend of SI contrast at different phases. CE-T₁WI, contrast-enhanced T₁-weighted images; SI, signal intensity.

Compared with CE-T₁WI_{-15 s}, the SI contrast of T₁WI to CE-T₁WI_{-20 min} decreased by (22.42±27.52)%, (39.60±30.42)%, (50.11±26.30)%, (58.65±26.01)%, and (77.43±31.19)%. The differences in the SI contrast between the different phases were statistically significant (P<0.05, Table S1).

Comparison of GTV volumes at different phases

The volume of GTV_-T1WI to GTV_{-20 min} was 15.56–23.05 cm³ (Table 3). Among them, the volume of GTV_-T1WI was the largest, whereas GTV_{-20 min} had the smallest volume (Figure 4). Compared with GTV_-15s, the volume reduction rate of GTV_{-45 s} to GTV_{-20 min} was 3.64–22.75%. The volume reduction rate was the smallest for GTV_{-45 s} and largest for GTV_{-20 min} (Table 3 and Figure 5). Except for comparisons between GTV_{-15 s} and GTV_{-45 s}, GTV_{-15 s} and GTV_{-75 s}, and GTV_{-45 s} and GTV_{-75 s}, the differences in the volume of GTV at other phases were statistically significant (P<0.05). Further details are provided in Table 3.

Figure 4 Schematic representation of GTV and DSC changes at different phases. DSC, Dice similarity coefficient; GTV, gross tumor volume; T₁WI, T₁-weighted images.

Figure 5 Schematic representation of volume differences between GTV_{-15 s} and GTV at different phases. (A,C-F) Volume difference display of GTV_-T1WI, GTV_{-45 s}, GTV_{-75 s}, GTV_{-150 s}, GTV_{-20 min} and GTV_{-15 s}; (B) tumor volume determined by GTV_{-15 s}. GTV, gross tumor volume; T₁WI, T₁-weighted images.

Comparison of shapes of GTV_{-15 s} and GTV at different phases

The trend in shape changes of the GTV across different phases compared with the GTV_{-15 s} aligned with the trend observed in volume changes (Figure 4). DSC values for GTV_-T1WI and GTV_{-45 s} to GTV_{-20 min} ranged from 0.64 to 0.79, with GTV_{-45 s} and GTV_{-20 min} exhibiting the largest and smallest DSC, respectively (Table 3 and Figure 6).

Figure 6 Schematic of tumor shape differences at different phases. (A-F) GTV_-T1WI-GTV_{-20 min} tumor shape display; (G) GTV_-T1WI-GTV_{-20 min} tumor shape comparison; (H) G magnified shape-difference display. GTV, gross tumor volume; T₁WI, T₁-weighted images.

The HD of GTV_-T1WI and GTV_{-45 s} to GTV_{-20 min} were 7.85–12.48 mm, among which GTV_{-45 s} and GTV_{-20 min} exhibited the smallest and largest HD, respectively (Table 3).

Discussion

Improving the accuracy of GTV determination is essential for improving the efficacy of radiotherapy (18,19). Accurate imaging and determination of the boundary between the tumor and surrounding normal tissue are crucial (19-21). CE-MRI offers superior soft tissue resolution, making it more effective than CE-CT for imaging tumor boundaries. After the contrast agent is injected into patients, it undergoes dynamic changes with blood flow, influencing the imaging of both the tumor tissue and surrounding normal pancreatic tissue, which in turn affects the accuracy of tumor boundary determination.

This study quantitatively analyzed the changes in the SI, volume, and shape of pancreatic cancer as observed on multiphase CE-MRI and confirmed that different enhancement phases significantly influence the imaging characteristics of the lesions. Additionally, 15 s after contrast agent injection, the SI contrast between the tumor tissue and surrounding normal pancreatic tissue was the highest, resulting in the clearest boundary imaging and complete visualization of the tumor tissue. Therefore, CE-T₁WI_{-15 s} is recommended as the optimal sequence for determining the GTV of pancreatic cancer based on CE-MRI.

The most notable difference between pancreatic cancer and other malignant tumors is the limited blood supply. This is primarily due to a strong connective tissue hyperplastic response, which results in significant fibrous interstitial deposition (22). This deposition compresses interstitial blood vessels, creating a hypovascular and hypoxic microenvironment within the tumor tissue. This characteristic underlies the significant differences in imaging performance between pancreatic cancer and normal pancreatic tissues across different phases.

Komar et al. (23) demonstrated that the blood flow in pancreatic cancer is approximately 60% lower than that in normal pancreatic tissue. Consistent with this finding, our study showed that the mean SI of pancreatic cancer tissue was lower than that of normal pancreatic tissue across all time phases. Furthermore, the rate of increase in the mean SI after contrast agent injection was significantly lower in pancreatic cancer than in normal pancreatic tissue, confirming the characteristic of reduced blood supply in pancreatic cancer.

Owing to the poor perfusion of the lesion, the amount of contrast agent delivered to the lesion via the blood was significantly reduced, while the amount flowing into the normal pancreatic tissue remained unchanged. Consequently, the lesion appeared to have a relatively low SI in the arterial phase. At this point, the SI contrast between the lesion and normal pancreatic tissue was the highest, and the boundary imaging was the clearest. This observation is consistent with the findings of previous studies (24,25).

The degree and range of enhancement in tumor and normal pancreatic tissues were influenced by factors such as blood flow, vascular permeability, diffusion rate between blood vessels and the interstitial space, and the dose and concentration of the contrast agent (26). The penetration and washout of contrast agents were part of a dynamic process. As time progresses, the amount of contrast agent penetrating the tumor tissue gradually increases beyond that observed at 15 s, leading to a slow increase in the mean SI of the lesion. By contrast, the contrast agent in normal pancreatic tissue began to clear after 45 s, resulting in a gradual decrease in the SI. Consequently, the difference between the lesion and normal pancreatic tissue diminished, reducing the contrast and causing boundary imaging to become less distinct. The relative enhancement of tumor tissue observed during the 150 s delay phase may be attributed not only to the conventional processes of contrast agent penetration and outflow but also to the accumulation of contrast agents in the extracellular space or disruptions in venous drainage (25).

When determining the tumor GTV, the high contrast between the tumor tissue and the surrounding normal tissue is a factor considered in selecting the appropriate sequence. To ensure the efficacy of radiotherapy, it is crucial to ensure that the GTV fully encompasses the entire tumor tissue. Failure to achieve this goal may increase the risk of recurrence. Unlike other abdominal organs, the pancreas is not encapsulated, making pancreatic tumors more likely to invade surrounding tissues and organs (25). Furthermore, chronic pancreatitis in some patients complicates the assessment of tumor boundaries.

This study found that GTV_-T1WI had the largest volume, followed by GTV_{-15 s} and GTV_{-45 s}. When determining the GTV based on T₁WI, the absence of contrast agent injection resulted in an equal SI between the tumor tissue and surrounding blood vessels, adjacent tissues, and organs, leading to unclear boundaries. This lack of clarity introduced determination errors, which were the primary reasons for the larger volume of the determined GTV. Although the tumor volume determined by GTV_-T1WI was the largest, caution remains necessary when using T₁WI alone to determine the GTV of pancreatic cancer because of its large determination error and low contrast.

The dynamic changes between tumor tissue and normal pancreatic tissue after contrast agent injection significantly influenced the determination of the GTV. This effect was demonstrated by the gradual decrease in GTV volume from GTV_{-15 s} to GTV_{-20 min} over time. Generally, as the time after contrast agent injection increased, the differences in volume and shape between the GTV and GTV_{-15 s} became more pronounced, making it increasingly difficult to determine the boundary and reducing the integrity of tumor imaging.

Additionally, we found that the determination error in the GTV_{-20 min} was primarily due to the small difference in the SI between the tumor tissue and normal pancreatic tissue, making it difficult to distinguish the boundary when determining the GTV. This contrasts with the determination errors observed in the GTV_-T1WI.

This study quantitatively analyzed the differences in pancreatic cancer imaging using multi-phase CE-MRI, confirming that early arterial enhancement at 15 s can improve the accuracy of GTV determination, providing a basis for GTV determination and MRI scan sequence selection. This method can reduce the total scan time and provides an intuitive and reliable approach for the application of daily MRI-guided pancreatic cancer single or few high-dose stereotactic body radiotherapy (SBRT). However, this study had some limitations. First, this study did not compare the dosimetric differences in the GTV across different phases. Second, multi-sequence scanning is time-consuming and requires high levels of respiratory coordination from patients, which can lead to poor patient tolerance.

Conclusions

In conclusion, this study demonstrates that the 15 s after contrast agent injection provides superior SI contrast and boundary definition compared with other phases. These findings strongly suggest that the CE-T₁WI_{-15 s} sequence could serve as an optimized timing for precise GTV determination, particularly under specific injection protocols. Further prospective studies are warranted to validate its routine clinical implementation.

Acknowledgments

The authors acknowledge financial support for their research work and contribution writing this paper from their sponsors.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2163/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2163/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2163/prf

Funding: This study was supported by the Taishan Scholars Project of Shandong Province (No. ts201712098).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-aw-2163/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study is a retrospective image data analysis, with all data anonymized, and does not involve experiments directly applied to humans, so informed consent is not required from patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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