Functional MRI for the prediction of treatment response in head and neck squamous cell carcinoma: potential and limitations
© The Author(s). 2016
Received: 18 February 2016
Accepted: 2 August 2016
Published: 19 August 2016
Pre-treatment or early intra-treatment prediction of patients with head and neck squamous cell carcinomas (HNSCC) who are likely to have tumours that are resistant to chemoradiotherapy (CRT) would enable treatment regimens to be changed at an early time point, or allow patients at risk of residual disease to be targeted for more intensive post-treatment investigation. Research into the potential advantages of using functional-based magnetic resonance imaging (MRI) sequences before or during cancer treatments to predict treatment response has been ongoing for several years. In regard to HNSCC, the reported results from functional MRI research are promising but they have yet to be transferred to the clinical domain. This article will review the functional MRI literature in HNSCC to determine the current status of the research and try to identify areas that are close to application in clinical practice. This review will focus on diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE–MRI) and briefly include proton magnetic resonance spectroscopy (1H-MRS)and blood oxygen level dependent (BOLD) MRI.
Head and neck squamous cell carcinoma (HNSCC) is the most common cancer in the head and neck. The two main modalities of treatment with curative intent for patients with advanced stage HNSCC are surgery or chemoradiotherapy (CRT). Over the past decade the non-surgical approach has become more popular because of the better organ preservation, but not all HNSCCs respond to CRT and approximately 25–30 % of patients will fail treatment at local or nodal sites in the head and neck. The successful pre-treatment identification of patients with resistant tumours in the head and neck would allow the CRT regimes to be modified or changed to a surgical approach. In addition intra-treatment scanning is already under evaluation to adapt radiotherapy (RT) fields to the changing size of the tumour  providing an opportunity to monitor early treatment response and adjust CRT regimes accordingly. Even if treatment is unaltered the identification of primary or nodal sites at risk of treatment failure would allow those sites to be targeted for more aggressive post-treatment investigation, so that residual cancers can be identified while they are still amenable to salvage surgery.
Computed tomography (CT), fluorine-18-fluorodeoxyglucose-positron emission tomography (18FDG-PET)/CT and magnetic resonance imaging (MRI) are used to identify resistant HNSCCs. All three imaging modalities are well established in routine clinical practice for staging head and neck cancer, planning treatment and assessing post treatment response. Each imaging modality has its own merits the discussion of which is beyond the scope of this review. This review will focus instead on MRI which produces both anatomical and functional information, and is ideally suited to serial scanning, including repeat scanning early in the course of treatment. In common with all anatomical-based imaging, the anatomical MRI sequences have limitations in predicting treatment response and in monitoring response, hence the current interest in adding functional-based MRI sequences to the standard MRI examination protocol.
Functional MRI head and neck cancer research has been ongoing for more than 10 years, but there are many challenges still to be faced before functional MRI can be transferred from the research to the clinical domain. This article will review the current status of functional MRI techniques in HNSCC for pre-treatment and early intra-treatment prediction of response, with the emphasis on diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE–MRI) and a brief inclusion of proton magnetic resonance spectroscopy (1H-MRS) and blood oxygen level dependent (BOLD) MRI.
Functional MRI in HNSCC
Functional MRI is a technically challenging examination to perform on patients with head and neck cancer, because acquisition is hampered by artefacts, including susceptibility artefacts and those related to movement from coughing, swallowing and breathing. Moreover, the acquisition parameters have yet to be standardized across centres, and even when similar protocols are used reproducibility can be problematic. Once the data has been acquired there is variability in the methods of analysis. This includes issues such as whether to analyse the primary tumour or nodal metastases, where to place the regions of interest (ROI), and whether to use programs that are developed “in-house” or by produced by the different vendors data. Data obtained from the entire tumour volume is more representative of the tumour, compared with data obtained from small ROIs within the tumour or from a ROI encompassing the largest cross-sectional tumour area, but even so most studies have reported only the mean value of the functional parameter, which does not fully reflect tumour heterogeneity. To analyse tumour heterogeneity pixel by pixel analysis is being used because it enables functional data to be displayed as a histogram and provides additional parameter measures such as percentiles, volumes of parameters in a defined range, and those measures that reflect the shape of the distribution curve. The drawbacks of these sophisticated methods of analysis are that they are more technically challenging and it is difficult to isolate a single functional parameter measure that consistently predicts outcome.
Furthermore, an array of treatment endpoints has been used to analyse the predictive value of each functional MRI parameter. These endpoints include a change in tumour size post-treatment which may not necessarily predict clinical outcome, and tumour relapse in the head and neck which preferably is assessed over a follow-up period of at least 2–3 years when the vast majority of resistant HNSCCs are known to recur. Relapse at specific primary or nodal sites in the head and neck are valuable endpoints for studies that are designed to influence intra-treatment adaptive therapies or identify sites at risk of post-treatment residual disease. These are the endpoints that are of greater interest to the radiologist and are especially valid for head and neck MRI. However, many studies use more general endpoints such as relapse at any site including distant sites, or survival including overall, disease-specific, disease-free, progression-free and local relapse-free survival.
In summary, for any given functional MRI technique variable methods are used for image acquisition, image analysis and data correlation. Literature comparison is therefore not straightforward because a range of different functional parameter measures, and their respective thresholds, have been reported as predictors of outcome based on a range of different treatment outcomes. It is also worth noting that many functional MRI studies do not incorporate non-radiological confounding factors into the analysis, such as the human papilloma virus (HPV) status, which is an important independent predictor of the HNSCC outcome. These issues will be further explored below in relation to each functional modality.
Diffusion-weighted imaging (DWI)
Pre-treatment DWI for prediction of treatment response
Most DWI studies exclude the macroscopic necrotic regions of a tumour from the analysis, but HNSCCs are still heterogeneous tumours and the use of the mean ADC value has limitations. To overcome these limitations further research is required to find ways to analyse different populations of tumour cells within HNSCC. This includes using parameters such as ADC min  with one recent study by Preda et al.  finding a high ADC min, obtained from one standard deviation below the mean, was a significant predictor of poor disease-free-survival.
There are three further variables that need to be considered when comparing the DWI results in the literature. The first variable relates to the head and neck tumour site chosen for data acquisition. A study by Noij et al.  in the same patient population found that data acquired from nodal sites were predictive of outcome, whereas data acquired from primary sites were not. The second variable relates to the choice of b values for DWI acquisition and analysis. Recent studies have shown that mean ADCs obtained from high b value ranges of 300/500–1000 s/mm2 (“pure” diffusion) are more predictive of treatment response than mean ADCs obtained from low b value ranges of 0–100/300 s/mm2 (“perfusion-related” diffusion) [10, 12]; but even within the higher range one study has shown mean ADCs are predictive at 0–750 s/mm2 but are not predictive at b 0–1000 s/mm2 ; and another study has shown mean ADCs are predictive at b 0–2000 s/mm2 but are not predictive at b 0–1000 s/mm2 . The third variable relates to the variability of ADC values with different MRI systems and sequences that has been reported in some studies . Therefore, further research includes identifying the best tumour sites in the head and neck to select for functional imaging, the optimum range of b values for DWI acquisition and analysis, and the optimum ADC parameters and thresholds.
Intra-treatment DWI for prediction of treatment response
Summary of the role of DWI
DWI research points to high pre-treatment mean ADC and a low % rise in ADC early intra-treatment being indicators of poor outcome. Intra-treatment scanning is likely to become more important in clinical management and one of the main advantages of DWI over DCE or PET/CT is that it does not require an injection of gadolinium or FDG. In this regard the early % change in mean ADC for predicting response at tumour sites in the head and neck is one of the most promising clinical applications for DWI, once a cut-off threshold has been confirmed. However, further work is needed to improve quality assurance across different MRI scanners, standardise the DWI protocol, especially in relationship to the choice of b values, and develop more sophisticated methods for analysing heterogeneous treatment induced changes. In addition, ongoing technological advances continue to reduce susceptibility and motion artefacts associated with DWI in the head and neck.
Dynamic Contrast-Enhanced MRI (DCE-MRI)
There is less reported research related to intra-treatment monitoring using DCE-MRI compared to DWI possibly because DCE-MRI requires an intravenous injection of a contrast agent. There is some early work in tumour xenografts to suggest a rise in tumour Ktrans may occur over the first few days of treatment , and in human subjects to suggest a rise in plasma flow at two weeks . It is postulated that an early rise in Ktrans is due to damage to the blood vessels causing them to temporarily become leakier, which potentially could increase the delivery of chemotherapeutic agents into the tumour. Indeed a few reports suggest a fall in Ktrans & area under the gadolinium concentration-time curve (AUGC) is associated with poor overall survival , while an early rise in blood volume is associated with local control . However, further research is required, especially as results may be influenced by different therapeutic modalities and regimes including the use of anti-angiogenic agents.
Summary of the role of DCE-MRI
DCE-MRI is an even more challenging functional technique to perform in patients with HNSCC than DWI, and it has a greater range of methods and functional parameters for analysis. Research points to better assess treatment responses in tumours with higher vascular-related parameters HNSCCs, a high pre-treatment Ktrans being predictive of a good response, although clinically useful thresholds have yet to be established. Intra-treatment monitoring is promising but still at a relatively early stage of research.
Proton Magnetic Resonance Spectroscopy (1H-MRS) and Blood Oxygen Level Dependent (BOLD) MRI
1H-MRS was one of the first functional techniques to be assessed in the characterisation of tumours in the head and neck, but it remains a challenging technique in this region of the body, and in regard to pre-treatment prediction and intra-treatment monitoring of response there is a paucity of a research in this area when compared to DWI and DCE-MRI. One in vitro study of tumour specimens by Bezabeh et al.  has shown significantly elevated pre-treatment choline-to-creatine ratios in a poor response group, but these findings could not be corroborated in an in vivo human study using choline-to-creatine ratios as well choline-to-water ratios . This latter study was also unable to show any predictive value for the 2 week intra-treatment scan .
Tumour hypoxia reduces the effectiveness of CRT and is associated with an unfavourable outcome in HNSCC . Tumour hypoxia may be evaluated by different techniques which include non-invasive in vivo MRI using BOLD which relies on the paramagnetic effect of blood deoxyhaemoglobin to decrease the signal intensity on T2* images. BOLD identifies changes in tumour oxygenation while breathing oxygen or carbogen, which increases diamagnetic oxyhaemoglobin leading to an increase in the signal intensity within the tumour on T2* images. Although BOLD imaging has been shown to be feasible [41, 42] and T2* quantitative imaging may be sensitive and reproducible  in HNSCCs the predictive value of BOLD MRI currently is unknown.
Functional MRI research has identified parameters that have the potential to predict CRT response in patients with HNSCC either before the start of treatment or during a course of treatment. High ADCs from DWI and low Ktrans from DCE-MRI in pre-treatment head and neck sites are associated with unfavourable treatment outcomes, but clinical thresholds have yet to be established and research into the optimum methods of data acquisition and analysis are still ongoing. In the future it is likely that intra-treatment scanning will become more important in clinical management allowing modification of CRT regimes or the cessation of ineffective treatments. In this regard DWI, which does not require an intravenous injection of an exogenous agent, is the most promising technique and current results suggest that those tumours with a low % rise in ADC early in the course of treatment are more likely to fail treatment than those tumours with a high % rise in ADC.
Future advances are likely to come from optimisation of acquisition protocols, the development of more sophisticated methods of analysis which take into account tumour heterogeneity and allow serial intra-treatment changes to be monitored, and multiparametric imaging combining not only the different functional MRI parameters but also PET parameters on the new PET/MRI systems. However, in order for functional MRI to make it into mainstream of cancer management it must to be reproducible across multiple centres. Working groups are looking into the quality assurance and standardization of methods, but more work is needed to set up acceptable guidelines as functional MRI evolves [44–46].
ADC, apparent diffusion coefficients; AUGC, area under the gadolinium concentration-time curve; CRT, chemoradiotherapy; DWI, diffusion-weighted imaging; DCE–MRI, dynamic contrast-enhanced MRI; HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus; MRI, magnetic resonance imaging; PKM, pharmacokinetic models; 1H-MRS, proton magnetic resonance spectroscopy; RT, radiotherapy; ROI, region of interest; Ktrans, the volume transfer constant between the blood plasma and extracellular extravascular space
We would like to acknowledge the assistance of Benjamin King Hong Law and Lok Yiu Wong in the literature search and preparation of the manuscript.
Availability of data and materials
ADK: Literature search, manuscript drafting and approval of final manuscript. HCT: Literature search, manuscript drafting and approval of final manuscript.
The authors declare that they have no competing interests.
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