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Published in final edited form as: Magn Reson Imaging Clin N Am. 2015 Sep 26;24(1):1–10. doi: 10.1016/j.mric.2015.08.001

Functional MRI techniques in oncology in the era of personalized medicine

Matthias R Benz 1,2, Hebert Alberto Vargas 1, Evis Sala 1
PMCID: PMC5031083  NIHMSID: NIHMS813160  PMID: 26613872

SYNOPSIS

DW and DCE MRI already contribute significantly to several aspects of personalized cancer medicine, namely diagnosis, treatment planning, response assessment, and prognosis. Nevertheless, the need for further standardization of theses imaging techniques is beyond question, and needs to be addressed. Whole body DW MRI is an exciting field, however future studies need to investigate in more depth the biologic significance of the findings depicted, their prognostic relevance and cost effectiveness in comparison to MDCT and PET/CT. New MR imaging probes such as targeted or activatable contrast agents and dynamic nuclear hyperpolarization show great promise to further improve the care of cancer patients in the near future.

Keywords: DWI, DCE, hepatobiliary contrast agent, SPIO, MRS, DNP

1. Introduction

The National Cancer Institute defines personalized cancer medicine as „a form of medicine that uses […] specific information about a person’s tumor to help diagnose, plan treatment, find out how well treatment is working, or make a prognosis“ (1). Functional imaging allows visual analysis and quantification of biological processes in vivo, such as tumor metabolism, chemical composition, and blood flow. Its most important strength in comparison to other laboratory based tests of tumor biology is its capacity for whole body imaging, to capture whole tumor heterogeneity in vivo, and the noninvasive assessment of (treatment related) changes over time. Genetic tumor analysis based on single/few tumor biopsy samples may not reflect intratumoral heterogeneity and phenotypic diversity. A study in primary renal carcinoma and associated metastatic sites revealed that intratumoral heterogeneity can lead to underestimation of the tumor genomic landscape represented from single tumor biopsy samples (2) and thus may contribute to treatment failure.

Multiple functional/molecular imaging technologies are available (3, 4), with positron emission tomography/computed tomography (PET/CT), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) being represented in clinical routine. Since these modalities image different biologic processes they have the potential to be used in conjunction rather than in competition with one another. Irrespective of their field of application the advantages of MRI in comparison to PET and SPECT relate to its high spatial and temporal resolution, the superior soft tissue contrast, the capacity of multiparametric imaging and the lack of ionizing radiation which is relevant in vulnerable populations such as children and women of child-bearing age (5), but might be less relevant in adult cancer patients who undergo chemo- and/or radiation therapy.

Several functional MRI techniques are being used to e.g. evaluate tissue organization with diffusion weighted imaging (DWI), to assess tumor vascularity with dynamic contrast enhanced (DCE) MRI, and to detect tumor metabolites using magnetic resonance spectroscopy (MRS)/spectroscopic imaging (MRSI) or dynamic nuclear polarization (DNP). In addition, several specific and non-specific MR contrast agents are clinically applicable or under investigation (3, 4). On T2*-weighted imaging hypoxia can be detected based on an increase in the transverse relaxation rate of water caused by the paramagnetic effect of endogenous deoxyhemoglobin using blood oxygen level dependent (BOLD) MR. This technique has been used for imaging tumor hypoxia and treatment response (6–8).

Radiogenomics is another exiting field that aims to correlate cancer imaging features and genetic data for the evaluation of imaging biomarkers. For example, imaging features extracted from MRI have been shown to be correlated with gene expression in breast cancer (9) and glioblastoma (10). Texture analysis describes mathematical parameters computed from the distribution of pixels and is a noninvasive method of assessing heterogeneity within the tumor. Features derived by texture analysis have for example been shown to act as a potential imaging biomarker of tumoral response to neoadjuvant chemo-/radiation therapy in rectal cancer (11).

2. Diffusion weighted imaging

DWI utilizes the incoherent three-dimensional motion of water molecules in vivo (Brownian motion) to generate contrast. The degree of water diffusion within intra-and extracellular fluid and between intra- and extracellular compartments is impeded by tissue cellularity, intracellular elements, membranes, and macromolecules (12). The motion of water molecules e.g. in tumor tissue, cytotoxic edema, abscess, and fibrosis is more restricted and displays higher DWI signal intensity. The apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion and is lower in tissue with restricted diffusion compared to normal parenchyma (Figure 1). ADC is expressed in units of mm2/s.

Figure 1.

Figure 1

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Pretreatment transverse T2-weighted image (A) showed a tumor focus in the left peripheral zone. The patient was treated with radiation therapy. An MRI was performed 2 years later due to rising PSA. A discrete abnormality was difficult to appreciate on the transverse T2-weighted images at this time (B), however the ADC map (b-values of b=0, 1000 s/mm2) (C) and the fused T2-weighted and DW MR images (D) clearly depict the presence of recurrent tumor.

Diffusion based contrast primarily depends on the selection of b values (the degree of diffusion weighting that is applied during image acquisition), with improved contrast to noise ratio at higher b values, at the expense of lower signal-to-noise ratios. In general, malignant tumors exhibit higher DWI signal and lower ADC values compared to normal/reactive tissue or benign tumors. DWI has been shown to improve detection and diagnostic accuracy in several primary malignancies, for example in prostate (13) or endometrial (14) cancer. DWI in conjunction with morphologic MR imaging sequences improves detection of metastatic spread to the peritoneal cavity (15), in particularly in gynecologic malignancies with a reported sensitivity and specificity for the detection of peritoneal implants of 90% and 95.5%, respectively (16).

In several studies lower ADC values have been associated with a more aggressive tumor (17–20). However, DWI signal intensity and ADC values are dependent on histologic characteristics such as tumor type, tumor grade/differentiation, and extent of necrosis (12). False negatives may occur particularly in well-differentiated tumors, in cystic or necrotic lesions. Abscess and infection might cause false positive findings.

Low pretreatment tumor ADC has been found to predict a favorable treatment response, for example in colorectal and gastric carcinomas (21, 22). This observation might be explained by the relationship between tumor necrosis and unfavorable patient outcomes.

Successful treatment is generally reflected by decreases in signal intensity on high b value images and corresponding increases in ADC values due to treatment induced necrosis, edema or cellular lysis; all of them induce an increase in water diffusion in the extracellular space. However, transient early decreases in ADC values can be seen after treatment (23).

The development of echoplanar imaging, high gradient amplitudes, multichannel coils, and parallel imaging facilitated DWI to be extended to whole body imaging (23) (Figure 2). Whole body DW MRI is an exciting field to image systemic disease such as multiple myeloma, lymphoma and leukemia, but also solid tumors with associated metastatic spread, particularly those involving the skeleton. Whole body DWI can provide complementary information to CT, PET/CT and SPECT or might be able to replace tests using ionizing radiation. However, published data on staging/restaging accuracy and treatment response assessment are limited. Whole body DWI for tumor staging has some limitations, especially with regards to the limited anatomical coverage for intravenous contrast-enhanced sequences. Some solutions have been proposed. For example Klenk et al (24) used ferumoxytol (AMAG Pharmaceuticals inc, Waltham, MA, USA) enhanced whole body DWI for staging of children and young adults with malignant lymphoma and sarcoma in comparison to 18F-FDG PET/CT. Ferumoxytol increases the signal intensity on T1-weighted and decreases the signal intensity on T2-weighted images (hereby improving the contrast between tumor and the reticuloendothelial system). The fusion of ferumoxytol-enhanced whole-body DWI scans with ferumoxytol-enhanced anatomical T1-weighted scans provided diagnostic images very similar to an 18F-FDG PET/CT scan with equivalent sensitivities, specificities, and staging results of both imaging modalities (24).

Figure 2.

Figure 2

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Bone scan (A), 18F-sodium floride PET (B), 18F-FDG PET (C), whole body DW MR (D), T1w MR (E), and b50/900 fused MR (F) of a patient with metastazied prostate cancer. All scans readily depicted a bone met in the right pubic bone (right arrows on all images). 18F-sodium floride PET (B) and whole body DW MR (D/F) detected an additional T1 low signal lesion in the left pubic bone suspicious for metastatic disease (left arrows on B, D, E and F). Degenerative 18F-sodium floride avidity of the spine (B).

Short- and midterm test-retest variability of repeated ADC measurements in a healthy population has been reported to be not significant with a mean coefficient of variation of 14% (25). However, the authors suggest that treatment effects of less than approximately 27% (1.96 × coefficient of variation) will not be meaningfully detectable (25). Interestingly this definition of tumor response is very similar to what was reported in several studies investigating metabolic tumor response by 18F-FDG PET and which was suggested as a cutoff in the recently introduced PERCIST criteria (26).

The lack of standardization and the limited published data on interscanner variability hinder the comparison of DWI results between studies. A recent prospective study (27) evaluated the variability of ADC values in various anatomic regions in the upper abdomen measured with systems from different vendors and with different field strengths. The authors found no significant differences between ADC values measured at 1.5T and at 3T in any anatomic region. However, in two of seven regions at 1.5 T (left and right liver lobes) and in four of seven regions at 3T (left liver lobe, pancreas, and renal cortex and medulla), intervendor differences were significant.

3. Dynamic contrast-enhanced MRI and MR contrast agents

Perfusion imaging

Extracellular paramagnetic gadolinium based contrast agents (EGBCA) distribute nonspecifically in the blood plasma and interstitial space and are administered to reduce the T1 relaxation time of nearby protons, and therewith increase the signal intensity on T1-weighted images. In oncologic imaging DCE MRI uses a bolus injection of EGBCA to acquire multiple serial images as the contrast agent passes through tissue to obtain information on altered blood flow and vascularization of tumors. The perfusion data extracted from DCE MRI can be investigated qualitatively (visual), in a semiquantitative or quantitative manner to obtain data on enhancement fraction and permeability, respectively. Most of the pharmacologic models used for the quantitative approach are based on determining the rate of contrast exchange between blood plasma and extracellular space using transfer rate constants, such as Ktrans (forward volume transfer constant) an kep (reverse reflux rate constant between extracellular space and plasma).

The absence of enhancement is a strong predictor of benignity in several tumors, e.g. in breast cancer (28), whereas the semiquantitative enhancement criterion that suggests malignancy is a rapid initial enhancement (Figure 3). Quantitative DCE MRI also allows differentiation of malignant from benign tumors as has been shown for example in adnexal masses (29). On the other hand, qualitative DCE MRI time curve type analysis was found to perform poorly for the differentiation of prostate cancer from healthy prostatic tissue (30). DCE is currently considered to add relatively little incremental value to the combination of T2w and DWI for the detection of prostate cancer, as reflected in the recently updated Prostate Imaging and Reporting and Data Systems: Version 2 (PIRADS v2.0), which ascribed DCE a minor role in determining the PIRADS Assessment Category when T2W and DWI are of diagnostic quality (31). The addition of DCE MRI to T2-weighted and DWI also did not contribute significant incremental value in the detection of locally recurrent prostate cancer after radiation therapy (32).

Figure 3.

Figure 3

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Patient with rising PSA after radical prostatectomy. Hypointense lesion in the right acetabulum (arrowhead) and enlarged left internal iliac lymph node (arrow) are suspicious for metastatic disease on T1-weighted MRI (A). DWI (B) and fused T2-weighted and DWI data (C) show hyperintense signal in the right acetabulum as well as in the left internal iliac lymph node. DCE MRI (D) shows early contrast media uptake of both lesions. The parametric map (E) and the time-signal intensity curve (F) confirm the early contrast media uptake.

Anatomic tumor size measurements using standard WHO, RECIST, and RECIST 1.1 criteria (33) have limitations, particularly in assessing early treatment response and in assessing the effects of molecularly targeted therapies and anti-angiogenic strategies that stabilize disease rather than induce fast tumor shrinkage. DCE MRI parameters can serve as predictive biomarkers and enable early treatment response assessment in patients who undergo treatment with anti-angiogenic drugs and other therapies (34–38). However, the clinical application of the potentially powerful biomarkers derived from DCE MRI has been limited by the lack of standardization to permit interscanner/interinstitutional comparison of DCE MRI studies. Initiatives such as the Quantitative Imaging Biomarker Alliance (39) will help to address these issues in the future.

Hepatobiliary contrast agents

Three hepatobiliary contrast agents (HBCA) have been developed for liver MR imaging: gadoxetic acid (Gd-EOB-DTPA; Eovist® (US), Primovist® (Europe, Australia)), gadobenate dimeglumine (Gd-BOPTA; MultiHance®), and Mangafodipir trisodium (Mn-DPDP; Teslascan®; marketing status: discontinued). Gd-BOPTA and Gd-EOB-DTPA are taken up to varying degrees by functioning hepatocytes via organic anion transporters and are subsequently excreted in the bile (Figure 4). The relatively stronger hepatic signal intensity and biliary tree enhancement of Gd-EOB-DTPA in comparison to Gd-BOPTA results due to approximately 50% and 3–5% of excretion via the bile route, respectively (40). T1 shortening of the liver and biliary tree results in an increased difference in signal intensity for nonhepatocellular lesions compared with normal liver background. Therefore, HBCA allow dynamic imaging in the arterial phase (20s p.i.), portal venous phase (60–70s p.i.) and late venous phase (2–3 min p.i.), as well as liver specific imaging with regards to a lesions hepatocyte function and hepatocyte content during the hepatobiliary phase (20 min p.i.) (41). The results of several studies have shown that MRI with HBCA depicts more metastatic lesions in the liver than contrast enhanced MRI with EGBCA and adds diagnostic information and confidence (42, 43). Gd-BOPTA and Gd-EOB-DTPA have been shown to be equivalent to EGBCA dynamic imaging for lesion characterization (44, 45). However, the relatively short bolus transit time due to the lower approved dose of Gd-EOB-DTPA (0.025 mmol/kg) in comparison to conventional EGBCA (1.0 mmol/kg) may result in weaker arterial enhancement of liver lesions and impaired lesion characterization. Therefore, the acquisition of the arterial phase needs specific attention and might benefit from modified injection strategies (46, 47). In addition, acute self-limiting dyspnea was observed significantly more often using gadoxetate disodium compared to gadobenate dimeglumine and might affect arterial phase MR image quality (48).

Figure 4.

Figure 4

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Hypervascular hepatic tumor (A), no washout of extracellular contrast agent (B) but hypointense on delayed hepatobiliary phase with Eovist (C). The biopsy was consistent with adrenocortical metastasis.

(Courtesy of Dr. Richard Kinh Gian Do, MSKCC)

Superparamagnetic particles of iron oxide (SPIO)

SPIO are composed of a crystalline iron oxide core (ferri(Fe3+)magnetic and ferro(Fe2+) magnetic material in the form of maghemite (γFe2O3) and magnetite (Fe3O4)) and a stabilizing coating material, usually made of low molecular weight dextran. SPIO are divided into different classes according to their global size: standard SPIO (SSPIO) have a diameter of >50nm, whereas SPIO with a diameter of <50nm are referred to as ultra small particles of iron oxide (USPIO). Due to their shortening of T2/T2* they are also known as negative, i.e. signal eliminating, contrast agents with darkening of the contrast enhanced tissue at a given echo time. However, enhancement on T1-weighted images can also be seen with the smaller nanoparticles. Various SPIO have been tested in clinical and preclinical settings (49).

The passive uptake of SPIO in the mononuclear phagocyte system or reticuloendothelial system after intravenous application has been shown to increase the sensitivity of detecting metastasis in the liver (50), the spleen (51), lymph nodes (52), and bone marrow (53).

Other MR imaging agents

Nanoparticles can also be targeted towards specific receptors or molecules by conjugating specific ligands to their surface such as antibodies, peptides, or small molecules (3).

Activatable MR contrast agents enable to induce an imaging signal only when a particular disease state is present (54, 55).

Due to the 100% natural abundance and relatively high sensitivity of 19F for MRI (83% to that of protons), 19F MRI has been used in preclinical and clinical studies to track drug biodistribution (56), and to assess regional tumor hypoxia amongst others (57).

Another example is chemical exchange saturation transfer (CEST) agents, where contrast enhancement is based on selectively reducing the magnetization of the water signal, with only minimal effect on its longitudinal relaxation rate (58). Multimodality probes aim to combine MRI with nuclear or optical imaging to obtain high spatial resolution and high sensitivity or enable preoperative staging and intraoperative molecular imaging (3).

4. Imaging of tumor metabolites using “traditional” magnetic resonance spectroscopy/spectroscopic imaging and dynamic nuclear polarization

“Traditional” magnetic resonance spectroscopy

MRS/MRSI permits noninvasive acquisition of signals from cancer metabolites. Accessible nuclei are e.g. 1H, 31P, 23Na, 19F, 13C (59), with differences in detectability and signal intensity related to variations in signal susceptibility, percentage isotope concentration, and tissue concentration. Clinical MRS/MRSI studies use signals from 1H nuclei of compounds in tissue since 1H nuclei provide the largest signal, and do not require hardware modification to the scanner (60). The major metabolites evaluated in 1H MRS include choline (cell membrane marker), creatine (energy marker), lipids (tissue breakdown and cell death), lactate (metabolic acidosis), and in the brain N-acetyl aspartate (normal neuronal marker) (61).

The metabolic fingerprints of several malignancies have been studied, however the main field of investigation is the brain (Figure 5), followed by prostate and breast imaging. Most brain tumors manifest with relative reduction of N-acetyl aspartate and elevation of choline. MRS in brain tumors has been shown to be a useful tool in the initial diagnosis, tumor grading, imaging guided biopsy, and treatment response assessment (62, 63). Elevated choline signal however can also be observed in other tumors, such as prostate cancer (64) and breast cancer (65). Early studies in prostate cancer reported an ability of MRS to help differentiate cancer from benign/necrotic tissue (66–68), however a prospective multicenter study, conducted by the American College of Radiology Imaging Network (ACRIN) reported that the addition of MR spectroscopic imaging to anatomic MR imaging did not improve the accuracy for localization of peripheral zone prostate cancer (69). In breast cancer, a prospective single center study reported that MRS in addition to DCE MRI and DWI improves the accuracy of breast cancer diagnosis (70). The evaluation of MRS using newer platforms with improved spatial and temporal resolution and comparisons to currently standard of care functional techniques such as DWI is warranted.

Figure 5.

Figure 5

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Single voxel spectroscopy in a FLAIR hyperintense IDH mutant low grade astrocytoma. The tumor (A) shows high choline (Cho, a cell membrane marker) at 3.2 ppm, low creatine (Cr, an energy marker) at 3.0 ppm, low N-acetylaspartate (NAA, a neuronal marker) at 2.0 ppm, and inverted lipid/lactate (LL, an anaerobic glycolysis marker) at 1.3 ppm. The high choline and lipid/lactate are consistent with malignancy. Using a variable TE1/TE2, a small 2HG (2-hydroxyglutarate, an oncometabolite formed exclusively by isocitrate dehydrogenase [IDH] mutant tumors) peak is also present at 2.25 ppm. Compare with normal spectrum seen in contralateral brain (B) with absent 2HG peak.

(Courtesy of Dr. Robert J. Young, MSKCC)

Dynamic nuclear polarization (hyperpolarization)

MRI signal intensity is proportional to the spin polarization (the difference in the fraction of nuclei aligned with or against an applied magnetic field). Since polarization is typically very small on the order of 0.0001% to 0.0005% depending on the nucleus and field, nuclei other than protons (with its high concentration in water and fat which overcomes poor polarization) are difficult to image using standard techniques (71). Hyperpolarization refers to a procedure that drives nuclei (such as 15N or 13C), temporarily, into a significant redistribution of the ordinary population of energy levels to gain signals 10.000-fold or more (71).

After the administration of a hyperpolarized agent (such as [1-13C] pyruvate) the agent’s delivery as well as its metabolic substrates can be monitored using MRI. Measurements of hyperpolarized 13C label flux between pyruvate and lactate in lymphoma (72) and glioblastoma (73) bearing mice has been shown to be able to detect response to chemotherapy. In addition, the amount of hyperpolarized lactate measured after injection of hyperpolarized [1- 13C] pyruvate showed great potential as a new biomarker capable of noninvasively grading prostate cancer in mice (74). The first in-man imaging study of MRI with hyperpolarized [1- 13C] pyruvate in 31 patients with untreated biopsy proven prostate cancer (75) confirmed the safety of the agent (no dose limiting toxicities were observed) and showed elevated [1- 13C] lactate/[1- 13C] pyruvate ratio in regions of biopsy proven prostate cancer (75).

5. Summary – functional MRI today and tomorrow

DW and DCE MRI already contribute significantly to several aspects of personalized cancer medicine, namely diagnosis, treatment planning, response assessment, and prognosis. Nevertheless, the need for further standardization of theses imaging techniques is beyond question, and needs to be addressed. Whole body DWI is an exciting field, however future studies need to investigate in more depth the biologic significance of the findings depicted, their prognostic relevance and cost effectiveness in comparison to MDCT and PET/CT. New MR imaging probes such as targeted or activatable contrat agents and dynamic nuclear hyperpolarization show great promise to further improve the care of cancer patients in the near future.

KEY POINTS.

  • ■

    Several functional MRI techniques are being used to detect biological processes in vivo, e.g. to evaluate tissue organization with DWI, to assess tumor vascularity with DCE MRI or tumor metabolites using MRS or DNP.

  • ■

    The most important strength of functional MRI is its capacity for whole body imaging, to capture whole tumor heterogeneity in vivo, and the noninvasive assessment of changes over time.

  • ■

    Standardization of these imaging techniques needs to be addressed in the future.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

DISCLOSURE STATEMENT

The Authors have nothing to disclose.

Contributor Information

Hebert Alberto Vargas, Email: vargasah@mskcc.org.

Evis Sala, Email: salae@mskcc.org.

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