Can preoperative liver MRI with gadoxetic acid help reduce open-close laparotomies for curative intent pancreatic cancer surgery?

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with an overall 5-year survival rate of approximately 8% (range 3-32% depending on the stage) [1]. Generally, surgical resection is the only potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC) [2] and unlike colorectal cancer, preoperative detection of liver metastasis (LM) precludes curative surgery. Since PDAC often presents late, only approximately 20% of patients are resectable at presentation, and in many, the disease has already metastasized [3, 4]. Contrast-enhanced computed tomography (CECT) is the most commonly used imaging modality for staging pancreatic cancer with its ability to detect local extension and distant metastasis [5, 6]. Unexpected adverse findings, in particular LM, have been reported intraoperatively in 8-26% with potentially resectable pancreatic cancer on CECT [7‐9], resulting in aborted surgeries [10]. Thus, it is of great relevance to detect LM on preoperative imaging to avoid futile (open-close) laparotomies and resultant associated postoperative morbidity/mortality and added hospitalization costs [11].

Gadoxetic acid (Gd-EOB-DTPA) is a hepatobiliary MRI contrast agent [Eovist (US) or Primovist (Canada, Europe), Bayer HealthCare, NJ, USA] with both extracellular and liver-specific properties. Its uptake by hepatocytes and biliary excretion enhances the contrast between the liver parenchyma and hepatic lesions, thereby improving liver lesion detection [12]. Some studies have reported the incremental value of Gadoxetic acid-enhanced liver MR (EOB-MRI) over CECT for detection of LM, particularly in colorectal cancer [13, 14]. It has recently been shown that even though EOB-MRI had similar performance to extracellular-enhanced MR imaging in detecting PDAC, it had greater sensitivity in detecting LM [15]. Although a few studies have evaluated the added value of EOB-MRI over CECT in identifying LM from pancreatic cancer [10, 11], specifically PDAC [16], assessment of direct impact on surgical management of PDAC is not well reported.

This study aimed to compare the diagnostic performance of EOB-MRI versus CECT in the preoperative detection of LM in patients being considered for curative-intent PDAC surgery and its impact on surgical planning and reduction of futile (open-close) laparotomies.

Curative-intent pancreatic cancer surgery was excluded in 15 patients [LM in 12, and vascular issues (occlusion or encasement by the primary tumor) in 3 patients]. Amongst 51 patients with attempted curative-intent surgery, 45 had successful surgeries, while 6 had open-close laparotomies. The reasons for open-close laparotomy were surface LM (n = 3), intraparenchymal LM (n = 2), and unexpected common hepatic arterial tumor encasement (n = 1). (Fig. 1) The mean size of LM discovered during surgery was 6.4 mm (2-10 mm). The intraparenchymal LM were retrospectively detectable only on MRI. Approximately 17% (11/66) of patients had received preoperative neoadjuvant chemotherapy for downstaging of vascular involvement before surgery. None of these patients had LM before starting the neoadjuvant chemotherapy. The mean time interval between neoadjuvant chemotherapy and preoperative imaging was 3.3 ± 1.3 months.

In the patient-level analysis of the formal imaging reports, the sensitivity of EOB-MRI for LM was significantly higher than CECT {70.6% (12/17) [46.6-86.8], vs 29.4% (5/17) [13.9-51.8], p = 0.002}. The specificity, positive and negative predictive values (PPV, NPV), and accuracy were 98% [87.7-99.7], 92.3% [55.2-99.1], 90.6% [74.9-96.0], and 90.9% [81.2-95.9] versus 100% [92.7-100], 100% [47.8-100], 80.3% [59.4-88.4], and 81.8% [70.7-89.4] for EOB-MRI and CECT, respectively. Although two patients were diagnosed with intraparenchymal LM on preoperative EOB-MRI, the clinical decision was to attempt surgery and perform excisional biopsies, which confirmed metastasis in both patients leading to open-close laparotomies (Fig. 2). Excluding these two patients from surgical exploration based on EOB-MRI would have further lowered the actual open-close laparotomy rate to 6.1% (4/66) from 9.1% (6/66). Among patients excluded from surgery due to LM (12/66), 10/12 patients with LM were identified by EOB-MRI while CECT identified only 5/12 patients. Thus, an incremental 7.6% (5/66) of patients were excluded from surgery due to LM detected only on EOB-MRI and CECT detected only 50% of the patients with LM compared to EOB-MRI. Two patients with LM were reported as indeterminate on both EOB-MRI and CECT. One of these patients had pancreatic tumor invading to portal vein confluence, and surgery was excluded on those grounds with follow-up imaging also indirectly confirming LM. In the other patient, percutaneous biopsy of an indeterminate liver lesion confirmed LM, thereby excluding surgery.

In the lesion-level analysis of retrospectively performed blinded independent readers’ observations 261 liver lesions were recorded 208 benign lesions (mean size, 7 mm; range 2-59 mm) and 53 metastases (mean size, 8.4 mm; range: 2-19 mm) in 66 patients as per reference standard, including. Reader 1 and 2 reported 40 and 36 LM respectively on EOB-MRI compared to 18 LM by both readers on CECT. Mean reader results revealed that 81% (43/53) of LM were diagnosed on EOB-MRI and 38% (20/53) on CECT. The overall sensitivity of EOB-MRI was significantly greater than CECT for both readers (mean, 71.7% [62.1-80.0] vs. 34% [25.0-43.8]; p = 0.009; R1, 75.5% [61.7-86.2] vs. 34% [21.5-48.3]; p = 0.009; R2, 67.9% [53.7-80.1] vs. 34% [21.5-48.3]; p = 0.018). Also, EOB-MRI had comparable mean specificity (98.6%, [96.9-99.5] vs. 100%, [99.1-100], and higher AUROC (85.1%, [80.4-89.9] vs. 66.9%, [60.9-73.1]) for LM detection. Table 3 illustrates the diagnostic performance of CECT and EOB-MRI as per two blinded independent readers. EOB-MRI detected additional LM (size range, 2-19 mm; 25 and 20 metastatic lesions for R1 and R2, respectively) compared to CECT. The number of small additional metastasis (≤ 1.0 cm) detected on EOB-MRI was 18 for reader 1 and 14 for reader 2. The number of LM ≤1.0 cm detected on EOB-MRI was significantly higher for both readers [R1, 60.4% (32/53) vs. 37.7% (20/53), p = 0.009; R2, 56.6% (30/53) vs. 35.8% (19/53), p = 0.008]. Moreover, the number of indeterminate lesions was lower on EOB-MRI compared to CECT for both readers, and this difference was statistically significant for one of the readers (R1: 6.1% (16/261) vs. 13.0% (34/261), p = 0.039; R2: 7.7% (20/261) vs. 14.9% (39/261), p = 0.081). Amongst 10 LM characterized as indeterminate on CECT by both readers, 80 and 50% of those lesions were accurately diagnosed on EOB-MRI as metastases by readers 1 and 2, respectively. (Fig. 3) The inter-reader agreement for diagnosis of LM was high on EOB-MRI [κ = 0.76 (95% CIs 0.594-0.926)], while it was excellent on CECT [κ = 0.855 (95% CIs 0.663-1.047)].

In a patient-level analysis of readers’ observations by considering only the presence or absence of LM, the sensitivity of EOB-MRI for detecting metastatic liver disease was again superior to that of CECT for both readers (R1, 75.4% [49.7-90.5] vs 35.3% [17.9- 57.7], p = 0.001; R2, 71.7% [45.1-88.6] vs 41.2% [19.6-66.8], p = 0.006). In addition, for both readers, the incidence of indeterminate diagnosis (score 3) was lower on EOB-MRI; and this difference between the two modalities was significant for reader 1 (R1, 13.6% [7.3-24.2] vs. 30.3% [20.5-42.4], p = 0.028; R2, 12.1% [6.2-22.4] vs. 21.2% [13-32.7]), p = 0.159). Table 4 demonstrates the potential change in surgical plan and reduction of futile open-close laparotomy rates based on each reader’s interpretation of EOB-MRI and CECT for LM. A potential 13.6% (R1, p = 0.008) and 10.6% (R2, p = 0.023) decrease in futile (open-close) laparotomies is realized when surgical planning included EOB-MRI instead of CECT alone. The inter-reader agreement for this simulated decision-making process was substantial for both CECT and EOB-MRI [κ = 0.744 (95% CIs 0.468-1.02) for CECT and κ = 0.691 (95% CIs 0.478-0.904) for EOB-MRI].

As per the current National Comprehensive Cancer Network (NCCN) guidelines (2021), the preferred imaging tool for pancreatic imaging is dual-phase pancreatic protocol CECT, whereas MRI is mostly used as a problem-solving tool (CT-indeterminate liver lesions, suspected tumor invisible on CECT, and contraindications for CECT, such as severe allergy to iodinated intravenous contrast material) [22]. However, there is a significant incidence of unnecessary laparotomy in up to 41% of patients with CT-defined resectable PDAC [5, 8, 9]. A meta-analysis assessing predicting resectability in patients with PDAC by CECT revealed a summary positive predictive value (sPPV) of 81%, indicating that 19% undergo surgical exploration only [5]. Considering the burden of cost and morbidity from futile surgery and the delay in the initiation of alternative treatments like chemotherapy, it is crucial to accurately select candidates for curative-intent surgery thereby decreasing the incidence of unnecessary laparotomies. Like MRI with extracellular contrast, MRI with liver-specific contrast could miss LM on dynamic arterial and portal phases. Yet, it can provide added value due to its hepatobiliary phase (HBP), in which both the hyper- and hypovascular metastases demonstrate hypointensity and increased conspicuity due to increased lesion-to-liver contrast. Generally, LM from PDAC are hypovascular and hypointense in arterial and portal-venous phases, and HBP could improve detection, thereby impacting surgical management. It has been shown that HBP can improve the detection of colorectal cancer LM, especially in the fatty liver or lesions smaller than 1 cm [13]. Our study demonstrates the beneficial impact of preoperative EOB-MRI on surgical planning due to its high diagnostic accuracy in LM detection with a potential reduction in the incidence of aborted curative-intent pancreatic cancer surgeries. At both patient and lesion levels, this study confirms superior sensitivity of EOB-MRI in depicting LM compared to that of CECT. Further, CECT was able to detect only half of the patients with LM compared to EOB-MRI. A few previous studies have reported the superior sensitivity of EOB-MRI in the detection of LM in pancreatic cancer [10, 11], specifically PDAC [16]. Motosugi et al. found that EOB-MRI was equivalent to CECT in depicting PDAC, and had a higher sensitivity for detecting LM [16]. Chew et al. reported sensitivity and specificity of 76.2 and 95.8% respectively for EOB-MRI in detecting LM in 69 patients with resectable pancreatic cancer on CECT, comparable with our mean reader results [11]. Ito et al. demonstrated that a significant predictor of LM was the identification of possible lesions on EOB-MRI, while other preoperative clinical factors, such as tumor markers and CECT findings were not predictive of LM [10]. Recently, a systematic review [23] reported that MRI was more sensitive than CT in detecting pancreatic cancer LM. This study supports our results; however, not all reviewed studies compared EOB-MRI with CECT in patients with PDAC while only two included studies performed MRI with a liver-specific agent in PDAC. Besides, this systematic review did not evaluate the impact of EOB-MRI versus CECT towards reduction of futile laparotomies. In our study, over one-tenth of patients with CT-defined resectable PDAC were incrementally detected to have LM on EOB-MRI rendering them unresectable. Mean reader results also revealed an incremental number of LM on EOB-MRI with apparent disease-free liver on CECT in a significant number of patients. Unlike CECT, EOB-MRI was able to correctly diagnose all patients with intraparenchymal LM, but similar to CECT, it failed to identify tiny liver surface metastases in a few patients leading to aborted surgery. These observations suggest that apart from small surface LM, EOB-MRI is highly reliable for detecting intraparenchymal LM in PDAC.

At a lesion level, our study showed that EOB-MRI had very high PPV and NPV for diagnosis of LM from PDAC. Likewise, at patient level, EOB-MRI had higher sensitivity and NPV than CECT for accurately identifying patients with LM. The high PPV of EOB-MRI for metastatic liver disease guides appropriate exclusion of curative-intent surgery in those patients, while the higher NPV compared to CECT can provide greater confidence towards proceeding with curative-intent surgery should there be no other contraindications. At lesion level, EOB-MRI was also significantly better than CECT in detection and characterization of small LM (≤1.0 cm). This result is also compatible with previous studies that evaluated the detection of LM on EOB-MRI [13, 24].

The incremental yield of EOB-MRI in detecting LM compared to CECT can reduce futile open-close laparotomies. Practically, in this study, surgery had been planned after the inclusion of both EOB-MRI and CECT findings. Therein EOB-MRI led to a two-fold exclusion of patients from attempted curative-intent PDAC surgery versus CECT due to detection of LM on EOB-MRI only. Additionally, the simulated rate of open-close surgery was significantly lower when the surgical plan was based on the detection of LM on EOB-MRI compared to CECT alone. This difference represents the potential incremental impact of EOB-MRI on clinical decision making and can reduce unnecessary open-close laparotomies. Additionally, reader interpretations of EOB-MRI demonstrated greater diagnostic confidence for lesion characterization with a lower incidence of indeterminate liver lesion diagnoses compared to CECT. Since conclusive preoperative imaging reports are, incontrovertibly, more helpful in making surgical decisions than those with indeterminate diagnosis, EOB-MRI further also helps in reducing diagnostic uncertainty regarding the presence or absence of LM during the preoperative clinical decision-making process.

Staging laparoscopy (SL) is not routinely utilized at our institution during the preoperative staging of PDAC. Although some NCCN member institutions routinely use laparoscopy before surgery or chemoradiation to rule out undetected metastases on imaging, there is a lack of consensus on the routine use of staging laparoscopy (SL) [25, 26]. Further, in most studies, the utility of SL was compared with preoperative CECT and not EOB-MRI. De Rosa et al. reviewed 24 studies assessing the utility of SL for CECT-defined resectable PDAC and demonstrated that the role of SL remains controversial. Although some of the advantages of SL include low rates of morbidity and mortality, and detection of peritoneal and liver surface metastases, it cannot adequately evaluate the posterior surface of liver or detect deeply located intraparenchymal LM with a false-negative rate of up to 9% having been reported [27]. In terms of cost-effectiveness, again, most studies have analyzed the cost-effectiveness of SL against the diagnostic performance of CECT and not EOB-MRI [28, 29]. In contrast, a retrospective indirect cost-effectiveness analysis of SL after MRI for pancreatic head carcinoma concluded that considering the paucity of missed metastases on MRI, the cost-effectiveness of SL is poor, and its yield is marginal. The NCCN panel suggests that SL can be considered for patients staged with resectable pancreatic cancer at increased risk for disseminated disease (markedly elevated CA 19-9, large primary tumors, large lymph nodes) and those with a borderline resectable disease before administration of neoadjuvant therapy [22]. In the future, it could be promising to assess if EOB-MRI can reduce the need for SL, consequently saving time, cost and potential morbidities.

Less than one-fifth of our patients had neoadjuvant chemotherapy, which may potentially increase the incidence of liver steatosis, and therefore decrease the sensitivity of CECT to detect LM. A previous study showed the superiority of EOB-MRI to CECT in the detection of small colorectal metastasis following chemotherapy, particularly in patients with hepatic steatosis [13]. They found a positive association between metastasis size of ≤1.0 cm detected only on EOB-MRI and the presence of hepatic steatosis. Our study did not find any significant increase in the presence of steatosis on chemical sift MRI versus CECT in those who had received chemotherapy. Therefore, we do not believe that neoadjuvant chemotherapy had significant influence on the results of our study.

Dual-energy CT (DECT), a relatively new imaging technology, allows characterization of tissue composition, such as calcium, iodine, and fat, and improves detection of pathologies by using two X-ray beams of different kVp energies [30, 31]. One of the stated benefits of DECT over conventional CT scan can be better characterization of small hypoattenuating liver lesions (cysts vs. LM) using iodine images. However, given limited availability and higher costs of DECT, it is not widely available for use in daily clinical practice. In the future, perhaps further studies directly comparing DECT with conventional CT scan or DECT with EOB-MRI might be valuable in preoperative surgical staging for patients with PDAC.

We must acknowledge some limitations of our study. First, this is a retrospective analysis with a relatively small patient cohort at a single site. However, all the study cohort patients underwent both EOB-MRI and CECT for direct head-to-head comparison of LM detection and impact on surgical decision-making process. In order to justify routine inclusion of EOB-MRI in all patients under consideration for curative pancreatic surgery, perhaps a prospective multi-center study with a larger cohort is required. Second, we did not specifically evaluate DWI diagnostic performance separately against the hepatobiliary phase of EOB-MRI. Our study aimed to perform a comprehensive evaluation of EOB-MRI rather than assessing portions of the MRI examination. A systematic meta-analysis assessing LM detection in patients with colorectal or non-colorectal cancer has shown lower sensitivity of DWI compared to EOB-MR imaging or the combination of both sequences in [32] with the latter having the highest sensitivity on a per-lesion basis. Finally, not all suspicious liver lesions were pathologically proven. If there were more than one suspicious liver lesion, tissue sampling would be performed first from the largest or the most accessible one, and further plans would be made accordingly. Disease progression on the subsequent follow-up imaging was used as a reference standard to confirm the metastatic nature of the unbiopsied lesions.

EOB-MRI provides superior diagnostic performance compared to CECT in the preoperative detection of LM from PDAC. Moreover, this incremental yield of EOB-MRI better informs the surgical decision-making process and can lower the incidence of failed curative-intent pancreatic surgery. Consideration should be given to inclusion of EOB-MRI in the preoperative assessment of PDAC deemed potentially resectable on CECT.