Marianthi-Vasiliki Papoutsaki1, Harbir Singh Sidhu1, Nikolaos Dikaios2, David Atkinson1, Timothy Beale3, Simon Morley3, Martin Forster4, Dawn Carnell5, Ruheena Mendes5, and Shonit Punwani1
1Centre of Medical Imaging, Division of Medicine, University College of London, London, United Kingdom, 2Centre for Vision, Speech and Signal Processing, University of Surrey, London, United Kingdom, 3Department of Radiology, University College Hospital, London, United Kingdom, 4Research Department of Oncology, University College Hospital, London, United Kingdom, 5Radiotherapy Department, University College Hospital, London, United Kingdom
Synopsis
Heterogeneity assessment and diffusion weighted magnetic
resonance imaging (DW-MRI) have been considered powerful diagnostic tools in predicting
chemoradiotherapy treatment outcome in patients with cancer. In this study,
pre-treatment microstructural heterogeneity derived by intra- and inter-voxel
MR diffusion rates was assessed in patients with neck squamous cell carcinoma
(HNSCC). A correlation was presented between
the pre-treatment MR diffusion heterogeneity and the chemoradiotherapy
treatment outcome of patients with HNSCC. Future work, to ascertain the mechanisms of these
correlations would open the opportunity to tailor therapies to individuals in
clinical practice.
Introduction
In oncology, diffusion weighted magnetic resonance
imaging (DW-MRI) and apparent diffusion coefficient (ADC) are considered
powerful diagnostic tools 1. ADC utility has been explored as
imaging biomarker for prediction and treatment response assessment in head and
neck squamous cell carcinoma (HNSCC) 2. However, ADC doesn’t provide
a breakdown across different sources of diffusion and is a broad representation
of all diffusion processes within a voxel. Heterogeneity has been suggested as
an important parameter in predicting outcome of cancer patients 3. MR
diffusion heterogeneity can be assessed: a) between voxels by the population
distribution of ADC parameters 4 and b) within voxels by alpha (a) value derived by stretched
exponential model 5 within an area of interest (ROI).Purpose
To determine whether pre-treatment microstructural
heterogeneity, reflected through intra- and inter-voxel MR diffusion rates, is correlated
with chemoradiotherapy treatment outcome of patients with HNSCC.Materials and methods
After institutional approval, 51 patients
with histologically confirmed HNSCC metastatic lymph node (N2/N3) disease were recruited prior chemoradiotherapy with their
informed consent. Inclusion criteria were 2-year of clinical, imaging and
histopathological follow-up. Exclusion criterion was poor image quality of MRI.
Based on multidisciplinary consensus review of the follow-up, patients were
categorised into post-therapy local complete response (CR) and nodal recurrent
disease (RD) depending on presence or absence of any local disease recurrence. To
compare microstructural heterogeneity between diseased and healthy nodes, 8
healthy volunteers were recruited. Patients (pre-treatment) and volunteers were
scanned on a 1.5T MR scanner (MAGNETOM Avanto, Siemens AG, Erlargen, Germany)
using carotid coils in supine position. Axial DW images were acquired covering
the base of skull to upper thorax (Table 1). Mono-exponential and stretched
exponential models were fitted to all b-values for each pixel (MATLAB 2016;
MathWorks Inc., Natick, MA). A radiologist drew ROIs on DW images (b=300s/mm2),
containing the metastatic node (Figure 1a) for patients and the nodal tissue of
one or more normal nodes for volunteers using Jim 5.0 software (Xinapse
Systems, Thorpe, Waterville, UK). The ROIs were transferred to the calculated
maps (Figure 1b-1d), ADC and distributed diffusion coefficient (DDC) histogram
distributions and median alpha (a) value were estimated for patients and volunteers and were
statistically compared (StataCorp 2013. Stata Statistical Software: Release 13.
College Station, TX: StataCorp LP).Results
After
the 2-year follow-up, 20 patients had confirmed local complete response (CR
patients) and 15 patients local nodal recurrent disease (RD patients). Median
ADC and DDC values didn’t present significant differences between the patient
groups (p=0.91 for ADC and p=0.92 for DDC comparisons) and between each patient
group and the volunteers (Figure 2). From ADC histogram analysis (Tables 2), skewness
was larger in CR group than in RD group, but not statistically significant
(p=0.25) and kurtosis was almost similar. The comparisons between each patient
group and the volunteers revealed significant differences in skewness (p<0.0001
between CR group and volunteers, p=0.02 between RD group and volunteers) and kurtosis (p=0.01 between each
patient group and volunteers). The ADC distributions were more skewed and more
“peaked” in patient groups than in volunteers. The DDC distributions exhibited
larger kurtosis for the RD patient group (Table 2), but not significant
(p=0.70), whereas skewness was almost similar between the two patient groups
(p=0.94). Significant differences were reported only in kurtosis between the RD
group and the volunteers (p=0.04). A significant difference (p=0.02) was
observed in median a values between the patients’ groups presenting increased
a values in RD than in CR group (Figure
3).Discussion
The pre-treatment median ADC values of CR patient
group were lower than in RD group and lower compared to volunteers, but not
significant, in agreement with reported trend towards increased ADC values in
non-responders 6. Since pre-treatment ADC distributions were
significantly more skewed and more “peaked” in patient groups than in healthy
volunteers, nodal disease could be identified by assessing inter-voxel
diffusion heterogeneity. This difference may be ascribed to inter-voxel
diffusion changes between diseased and normal nodes. The increased skewness in
patient groups may be interpreted as an increase in voxels with high
cellularity compared to healthy volunteers. Significantly higher pre-treatment median
a values were presented in RD group
than in CR and volunteers; although no significance difference was presented
between volunteers and patient groups. A higher a value in RD patients supports more
homogeneity in diffusion coefficients, reflecting less heterogeneity caused by
intravascular perfusion and extravascular diffusion processes existing within
the same voxel.Conclusion
Our quantitative analysis of pre-treatment DW-MRI suggest
that assessment of intra-voxel and inter-voxel MR diffusion heterogeneities by stretched
exponential and mono-exponential models can correlate with chemoradiotherapy
treatment outcome of patients with HNSCC.Acknowledgements
This research was supported by grants from the KCL/UCL
Comprehensive Cancer Imaging Centre and the UCLH NIHR Biomedical Research
Centre.References
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