Noninvasive Assessment of Tumor Microenvironment Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging and ¹⁸F-Fluoromisonidazole Positron Emission Tomography Imaging in Neck Nodal Metastases

Purpose

To assess noninvasively the tumor microenvironment of neck nodal metastases in patients with head-and-neck cancer by investigating the relationship between tumor perfusion measured using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and hypoxia measured by ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) positron emission tomography (PET).

Methods and Materials

Thirteen newly diagnosed head-and-neck cancer patients with metastatic neck nodes underwent DCE-MRI and ¹⁸F-FMISO PET imaging before chemotherapy and radiotherapy. The matched regions of interests from both modalities were analyzed. To examine the correlations between DCE-MRI parameters and standard uptake value (SUV) measurements from ¹⁸F-FMISO PET, the nonparametric Spearman correlation coefficient was calculated. Furthermore, DCE-MRI parameters were compared between nodes with ¹⁸F-FMISO uptake and nodes with no ¹⁸F-FMISO uptake using Mann-Whitney U tests.

Results

For the 13 patients, a total of 18 nodes were analyzed. The nodal size strongly correlated with the ¹⁸F-FMISO SUV (ρ = 0.74, p < 0.001). There was a strong negative correlation between the median k_ep (redistribution rate constant) value (ρ = −0.58, p = 0.042) and the ¹⁸F-FMISO SUV. Hypoxic nodes (moderate to severe ¹⁸F-FMISO uptake) had significantly lower median K^trans (volume transfer constant) (p = 0.049) and median k_ep (p = 0.027) values than did nonhypoxic nodes (no ¹⁸F-FMISO uptake).

Conclusion

This initial evaluation of the preliminary results support the hypothesis that in metastatic neck lymph nodes, hypoxic nodes are poorly perfused (i.e., have significantly lower K^trans and k_ep values) compared with nonhypoxic nodes.

Introduction

The use of multimodality imaging is rapidly gaining acceptance in oncology for the study of tumor microenvironment characteristics, including tumor vascular/perfusion status and tumor cell hypoxia, which have been shown to be related to treatment outcomes (1). Multimodality imaging allows the acquisition of both functional and anatomic images by exploiting the unique strengths of different imaging techniques (1). The present study focuses on the application of multimodality imaging techniques using gadopentetate dimeglumine (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and ¹⁸F-fluoromisonidazole (FMISO) positron emission tomography (PET) in studying neck nodal metastases.

Dynamic contrast-enhanced MRI is a useful noninvasive method for characterizing the pathophysiologic microenvironment of tumors (2) and involves assessing changes in signal intensity over time. With proper compartmental modeling, using models like the Brix-Hoffmann model (3), the modified analysis by Port et al. (4), or the Tofts model (5), the data may yield results on tumor-vessel permeability, tumor perfusion, and extracellular–extravascular volume fraction (i.e., data related to the tumor microenvironment) (6). On the other hand, hypoxia imaging has been most extensively studied with ¹⁸F-FMISO PET in the clinical setting 7, 8. This fluorinated radiotracer was developed from the nitroimidazole compound misonidazole as a hypoxic cell radiosensitizer (9). It is thought to be a surrogate imaging marker for hypoxia 7, 8, 10.

Dynamic contrast-enhanced MRI and ¹⁸F-FMISO PET are typically acquired and assessed separately. In a recent study of an animal tumor model, Cho et al. (11) found a negative correlation between perfusion as assessed by DCE-MRI and hypoxia as measured by late ¹⁸F-FMISO PET uptake, hence providing the evidence for the hypothesis that poorly perfused tumors are hypoxic (12). The study also established the utility of combined MRI and PET measurements for imaging the tumor microenvironment and identifying regions of tumor hypoxia and well-perfused tissue (11).

Clinical studies in head-and-neck (H&N) cancers have assessed perfusion or hypoxia separately 7, 8, 13, 14, 15, 16, 17, 18. Hoskin et al. (14) performed DCE-MRI on 13 H&N cancer patients before and after radiotherapy and suggested that treated patients in whom tumors have high MR signal enhancement might be considered for dose escalation. Rasey et al. (8) found marked intra- and intertumor variability of hypoxia and emphasized that complete, noninvasive hypoxia measurements in individual tumors are important for patient-specific treatment planning. Recently, Lee et al. (7), using the same radiotracer, illustrated the feasibility of dose escalation of the gross tumor volume in H&N cancer patients.

Several investigators have reported tumor oxygenation (using invasive Eppendorf pO₂ measurements) in H&N cancers to be associated with poor outcome 19, 20. Nordsmark et al. (20) performed pretreatment measurements of tumor oxygen tension in a multicentric trial with 397 H&N cancer patients and showed that tumor hypoxia is associated with a poor prognosis. Thus, the detection and quantification of hypoxia might provide a prerequisite for the clinical implementation of hypoxia-directed therapies that could potentially improve outcomes in H&N cancer patients (21). Although often considered the gold standard, invasive Eppendorf pO₂ histography has disadvantages: it is limited by sampling, unable to differentiate hypoxic and necrotic tissue, and cannot access all tumors. In contrast, ¹⁸F-FMISO PET is only sensitive to the presence of hypoxia in viable cells, can cover the entire region of interest, and is well tolerated by patients (22). The imaging techniques Gd-DTPA–based DCE-MRI and ¹⁸F-FMISO PET have been proposed separately as promising tools for predicting treatment response for H&N cancer 7, 8, 14, 17. As yet, however, no clinical studies have compared data from these modalities for assessment of the tumor microenvironment. The purpose of our study was to assess noninvasively the tumor microenvironment of neck nodal metastases in patients with H&N cancer by investigating the relationship between tumor perfusion measured using DCE-MRI and hypoxia measured by ¹⁸F-FMISO PET.