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Transl Oncol. Dec 2013; 6(6): 670–675.
Published online Dec 1, 2013.
PMCID: PMC3890701

Accurate Prediction of Nodal Status in Preoperative Patients with Pancreatic Ductal Adenocarcinoma Using Next-Gen Nanoparticle1

Abstract

OBJECTIVE: The objective of this study is to assess lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) in identifying malignant nodal involvement in patients with pancreatic ductal adenocarcinoma. METHODS: Magnetic resonance imaging was performed in 13 patients with known or high index of suspicion of pancreatic cancer and who were scheduled for surgical resection. Protocols included T2*-weighted imaging before and after administration of Ferumoxytol (Feraheme) for the evaluation of lymph node involvement. Eleven of the 13 patients underwent a Whipple procedure and lymph node dissection. Nodes that lacked contrast uptake were deemed malignant, and those that demonstrated homogeneous uptake were deemed benign. RESULTS: A total of 264 lymph nodes were resection, of which 17 were malignant. The sensitivity and specificity of LNMRI was 76.5% and 98.4% at a nodal level and 83.3% and 80% at a patient level. CONCLUSION: LNMRI demonstrated high sensitivity and specificity in patients with pancreatic ductal adenocarcinoma.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. In 2013, it is estimated that a total of 45,220 patients will be diagnosed with pancreatic cancer and 38,460 will die of this disease in the United States [1]. Surgical resection through pancreatectomy remains the most viable curative option despite inroads into better understanding of the molecular biology of PDAC [2], emergence of targeted drugs [3,4], intensity-modulated radiotherapy [5–7], and neoadjuvant chemotherapy regimen [8,9]. In parallel, advanced imaging methods including high-resolution computed tomography (CT) scanning, magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound have contributed to selecting patients for surgery while minimizing unnecessary surgeries.

One area where the new technologies have had less impact is with minimal disease that has spread to locoregional lymph nodes. This is not entirely surprising given the relatively low spatial resolution and limited tissue characterization of clinical imaging tools. One way to improve detection levels is by using radiotracers with high affinity for cancer cells and lack of distribution to normal surrounding tissues. This strategy has been successful for certain types of cancers [10] but unfortunately not for PDAC. The reasons are multifactorial but include extensive stromal components [11–13] and the lack of uniformly expressed biomarkers [14]. An alternative strategy to detect nodal disease has been to target host cells in lymph nodes, for example, by targeting nodal macrophages [15]. However, these previously tested magnetic nanomaterials have been discontinued and were never studied in PDAC.

One of the initial studies on lymphotropic nanoparticle-enhanced MRI (LNMRI) was performed on 80 patients with prostate cancer and found that the sensitivity of LNMRI was 90.5%, which was significantly higher than that of conventional MRI (sensitivity, 35.4%) [15]. Similar improved sensitivities in identifying malignant lymph nodes were found in many other malignancies such as gastric cancer [16], breast cancer [17], and endometrial and cervical cancers [18]. More recently, the role of LNMRI in the management of cerebrovascular lesions is under investigation. A recent study concluded that intracranial aneurysms with early uptake of ferumoxytol on MRI, and thus detecting the activity of macrophages in the aneurysm walls, were prone to rupture and thus may warrant early operative intervention [19]. Furthermore, LNMRI may also have a role to play in imaging aspirin effect on macrophages localized in the wall of the cerebral aneurysm [20].

The goal of the current study was to prospectively test a recently Food and Drug Administration (FDA)-approved nanoparticle developed for iron replacement therapy, Ferumoxytol (Feraheme; AMAG Pharmaceuticals, Lexington, MA), which has residual magnetic properties to be detectable by MRI. The long-circulating carboxymethyl dextran-coated iron oxide ((FeO)1 - n(Fe2O3)n) nanoparticle slowly extravasates, is thus delivered to lymph nodes by lymphatics, and is internalized into macrophages, presumably through macropinocytosis. We hypothesized that disturbances in lymph flow or in nodal architecture caused by metastases lead to abnormal nanoparticle accumulation patterns, detectable by MRI. We therefore performed a prospective phase 2 study to determine the efficacy of the nanoparticle-enhanced MRI approach. We enrolled patients with biopsy-proven PDAC undergoing surgery and compared preoperative MRI appearance of lymph nodes to histopathologic analyses.

Materials and Methods

Subjects

This exploratory study was performed as a prospective, single-dose pilot study and was approved by the Institutional Review Board. All patients with known or high index of suspicion of pancreatic cancer and who were scheduled for surgical resection were eligible for enrollment in this study. Patients underwent a CT of the chest, abdomen, and pelvis before enrollment to exclude distant metastases. Other entry criteria included the following: age > 18 and no evidence of iron overload. Subjects with a known iron allergy were also excluded.

The study group consisted of 13 patients (6 males and 7 females) with a mean age of 64 years, range 40 to 91 years. Patient characteristics are summarized in Table 1. Five patients underwent preoperative chemoradiation. Eleven patients underwent surgery with an average of 23 lymph nodes resected, range 7 to 42. In total, 264 lymph nodes were resected and available for analysis. In two patients, liver metastases were identified on the preoperative LNMRI, and therefore, they did not undergo resection.

Table 1
Overview of Population.

Study Procedure

Nanoparticle. Ferumoxytol (Feraheme; AMAG Pharmaceuticals) is a newer FDA-approved USPIO with a particle size of 17 to 31 nm and a molecular weight of 731 kDa. It comprises a nonstoichiometric magnetite core of approximately 6.8 nm in diameter, and to protect the bioactive iron, a semisynthetic carbohydrate coating of polyglucose sorbitol carboxymethyl dextran covers it. Ferumoxytol is approved for human use in the United States by the FDA for the treatment of iron deficiency anemia in adults with chronic renal disease and is available as a sterile neutral liquid providing a total of 510 mg of elemental iron in 17 ml.

All subjects received ferumoxytol IV in a calculated dose of 6 mg/kg of body weight with a maximum dose of 510 mg. The decision to inject 6 mg/kg was based on a prior study where 4 mg/kg was injected. However, the degree of uptake in normal nodes was less pronounced compared to an earlier nanoparticle, ferumoxtran-10 [21]; 6 mg/kg is a higher dose than in the prior study but less than the therapeutic dose, which is 8 mg/kg.

Magnetic resonance imaging. MRI of the upper abdomen (T1-, T2-, and T2*-weighted sequences) was performed on a 3T system (Siemens, Erlangen, Germany) using an eight-channel phased array coil. Ten patients underwent MRI before, immediately after, and 48 hours after the IV administration of ferumoxytol, whereas three patients only had imaging 48 hours after the IV administration of ferumoxytol. Quantitative T2* sequences were performed as breath-hold, monopolar, multiecho, gradient echo sequences with six in-phase, equally spaced echoes [echo time (TE) = 2.5–14.8 ms; repetition time (TR) = 169 ms; thickness = 4 mm] in all patients. Imaging time ranged from 35 to 45 minutes.

Image Analysis

The gradient echo (GRE) T2*-weighted sequences were reviewed by a radiologist before the patient underwent surgery. The reviewer used established diagnostic guidelines for subjective nodal characterization as outlined in an article by Saksena et al. [22]. Nodes were considered involved with metastatic disease if greater than 50% of the node has an area of high signal intensity on the post-contrast images, based on visual inspection.

Signal-to-noise ratios (SNRs) of the lymph nodes were determined on T2*-weighted images by placing operator-defined region of interest. SNR was determined by dividing the mean signal intensity of a lymph node by the SD of background noise. The paired Student's t test was used to evaluate the statistical difference between benign and malignant lymph nodes before and after administration of ferumoxytol.

Surgery and Pathologic Analyses

When reviewing the MRI images, lymph node location was divided into six regions: 1, porta hepatis; 2, posterior to pancreas; 3, anterior to pancreas; 4, along superior mesenteric vein; 5, along celiac axis and superior mesenteric artery; and 6, other. Before surgery, the imaging findings were discussed with the surgeon in case the lymph node dissection had to be extended to include nodes that were positive on the nanoparticle-enhanced MRI and would normally be beyond the dissection.

Following resection, the pathologic and imaging findings were compared on a regional basis. If the number of pathologically involved lymph nodes in a region correlated with the number of nodes considered positive on the nanoparticle-enhanced MRI, they were considered as true positives. Conversely, if there were only benign lymph nodes identified in any region on pathology and there were no lymph nodes considered positive on nanoparticle-enhanced MRI in the same region, all lymph nodes identified on MRI were considered true negatives. If there was discordance between the numbers of positive lymph nodes on nanoparticle-enhanced MRI and pathology in any region, they were considered either false positive (positive on MRI but negative on pathology) or false negative (negative on MRI but positive on pathology).

Statistics

Primary efficacy parameters such as sensitivity, specificity, negative and positive predictive values, and accuracy were performed at nodal and patient levels. A P value < .05 was considered significant.

Results

Ten patients received dual MRI scans before and 48 hours after bolus IV administration of the nanoparticle solution, and three patients only had an MRI 48 hours after administration of the nanoparticle solution. All patients tolerated the procedure and injections well, and there were no side effects. Table 1 summarizes the demographics. The nanoparticle administration resulted in expected lower signal in organs rich in phagocytic cells such as liver, spleen, and bone marrow. Because of this profound change, two patients had unexpected liver metastases revealed and which were not identified on the noncontrast MRI scans. These patients were therefore not eligible for a subsequent Whipple operation.

Eleven patients underwent a Whipple resection, and a total of 264 lymph nodes were resected, locoregionally mapped, and then individually analyzed for metastases by histopathology (Table 2). Of these analyzed nodes, 17 malignant lymph nodes were identified (6.4%). The lymph nodes were not grossly enlarged and thus did not meet size criteria for macrometastases [23]. The mean short-axis diameter of benign nodes was 5.5 mm ± 1.5 (range, 3–8.9 mm), and the mean short-axis diameter of malignant nodes was 4.1 mm ± 0.96 (range, 3.2–6.3 mm).

Table 2
Patient Characteristics.

MRI showed the small lymph nodes in expected regions around the pancreas. Similar as in liver and spleen, nodal signal intensity decreased on IV administration of the magnetic nanoparticle. Figure 1 summarizes the signal intensities of benign and malignant lymph nodes before and after the administration of ferumoxytol. On noncontrast scans, benign and malignant nodes had similar SNR (P = .777). Following IV administration of ferumoxytol, the SNR of benign lymph nodes (10.17 ± 3.5) was much lower compared to the SNR of malignant nodes (81.93 ± 8.5; P < .0001). Figures 2 and and33 summarize some of the typical imaging findings underlying the quantitative measurements.

Figure 1
Scatter plot comparing the SNR of benign and malignant lymph nodes before and after the administration of ferumoxytol.
Figure 2
Benign lymph node. (A) Axial contrast-enhanced CT image shows a subcentimeter posterior pancreatic node (arrow). (B) Axial precontrast gradient-echo image shows a hyperintense portocaval node (arrow). (C) Forty-eight hours after ferumoxytol, the node ...
Figure 3
Malignant lymph node. (A) Axial precontrast gradient-echo image shows a hyperintense peripancreatic node (arrow). (B) Forty-eight hours after ferumoxytol, the node shows no signal change indicating malignant infiltration. (C) Subsequent pathologic evaluation ...

At a nodal level, the sensitivity and specificity of lymphotropic nanoparticle-enhanced MRI was 76.5% and 98.4%, respectively. At a patient level, the sensitivity and specificity were 83.3% and 80%, respectively. In one patient, a single node was incorrectly called positive based on imaging findings, and in another patient, a histologically proven metastatic node was not identified. Table 3 summarizes the statistics of nodal staging.

Table 3
Statistics of MRI.

Discussion

In our study, LNMRI had a sensitivity and specificity of 83.3% and 80% at the patient level and 76.5% and 98.4% at the nodal level. Conventional cross-sectional imaging (CT, MRI, and PET/CT) has been found to have a sensitivity of 0% to 42% in nodal staging of pancreatic cancer [24–26]. In our patient cohort using a 1-cm short-axis diameter threshold, or even the more conservative 8-mm threshold [23], none of the malignant nodes would have been correctly characterized. With the administration of a lymphotropic nanoparticle, the sensitivity increased from 0% to 76.5%. LNMRI correctly identified five of six patients with pathology-proven lymph node involvement. It failed to identify nodal involvement in one patient in which there was a very small metastatic focus in one lymph node (Figure 4). Alternatively, in the only case where LNMRI falsely diagnosed lymph node involvement on pathologic review, it was nodular extension of the primary tumor rather than an involved lymph node (Figure 5).

Figure 4
(A) Axial gradient-echo image 48 hours after ferumoxytol administration shows a posterior lymph node that has homogenously low signal (arrow) consistent with a negative lymph node. (B) Subsequent pathologic evaluation found a small cluster of malignant ...
Figure 5
There is a nodular area of high signal intensity (arrow) adjacent to the pancreatic mass on the precontrast T2-weighted image (A). This nodule did not change signal between the pre-ferumoxytol administration and 48 hours post-ferumoxytol administration ...

It has been widely documented in the literature that lymph node status is one of the most important independent prognostic factors of survival, in particular, for resectable cases. Studies have found that the number of positive lymph nodes [27,28], lymph node ratios (number of lymph nodes involved to number of lymph nodes examined) [29–32], and site of lymph node metastases [33–36] may be more powerful predictors of postoperative survival than simple lymph node status (e.g., negative or positive). A recent surgical study has found that the number of lymph nodes examined affects, albeit differently, the prognostic accuracy of the number of positive nodes and the lymph node ratio [37].

The ability to preoperatively identify metastatic lymph nodes and their location in patients with PDAC would alter management in these patients, possibly making an extended lymphadenectomy necessary or systemic therapy a better treatment option. LNMRI may also have a role to play in identifying appropriate patients to receive neoadjuvant therapy and in guiding radiation therapy by mapping complete nodal status. The ability to identify the presence of lymph node metastases in various other malignancies, such as breast cancer and testicular cancer, is crucial for selecting the correct surgical approach and for deciding whether chemotherapy, radiotherapy, or neoadjuvant treatment should be given.

A limitation of our study is the small number of patients that underwent surgery; although 13 patients were enrolled, only 11 underwent surgery. However, a total of 264 lymph nodes were evaluated in these patients, allowing for more robust evaluation of this imaging technique. Because of the small number of malignant lymph nodes, there might have been bias toward higher specificity. Another limitation is that direct node-to-node comparison could not be made between the MRI and the surgical specimen; however, the nodes at each site were counted and characterized as benign and malignant and compared with the MRI.

Our study has shown that nanoparticle-enhanced MRI is an accurate and safe method for detecting nodal metastases in patients with pancreatic cancer.

Acknowledgments

We thank Sandeep Hedgire and Azadeh Elmi for all their help in enrolling patients and performing the scans.

Footnotes

1We thank GI Spore for financial support.

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