Trang Thanh Pham1,2,3,4,5, Gary Liney1,3,4, Karen Wong1,3,4, Christopher Henderson3,5,6, Robba Rai1,3, Petra L Graham7, Malcolm Hudson7,8, Nira Borok9, Minh Xuan Truong9, Mark Lee1,3, Joo-Shik Shin6, and Michael B. Barton 1,3,4
1Radiation Oncology, Liverpool Cancer Therapy Centre, Liverpool Hospital, Sydney, Australia, 2Sydney West Radiation Oncology Network, Westmead, Blacktown and Nepean Hospitals, Sydney, Australia, 3Faculty of Medicine, University of New South Wales, Sydney, Australia, 4Ingham Institute for Applied Medical Research, Sydney, Australia, 5School of Medicine, Western Sydney University, Sydney, Australia, 6Anatomical Pathology, Liverpool Hospital, Sydney, Australia, 7Department of Statistics, Macquarie University, Sydney, Australia, 8NHMRC Clinical Trials Centre, Sydney, Australia, 9Radiology, Liverpool Hospital, Sydney, Australia
Synopsis
This
study investigated 3D quantitative histogram assessment of diffusion weighted
imaging (DWI) and dynamic contrast enhanced (DCE) MRI in the prediction of
chemoradiotherapy (CRT) response in locally advanced rectal cancer.
Histopathologic response assessment was centralised and defined according to
AJCC tumour regression grade. A whole tumour histogram analysis and combined
multiparametric scatterplots of ADC and Ktrans were used to assess tumour
heterogeneity and prediction of CRT response. Post-CRT ADC 75th and
90th histogram quantiles were the most promising parameters for
prediction of CRT response. However, DCE-MRI and multi-parametric scatterplots
combining ADC and Ktrans did not add value in predicting response.
Introduction
Imaging
prediction of chemoradiotherapy (CRT) response in locally advanced rectal
cancer would enable stratification of management. Tumours are heterogeneous in
their response to treatment and summary measures such as mean ADC or Ktrans
do not reflect tumour heterogeneity. 3-dimensional (3D) MRI with a quantitative
histogram analysis may better depict subtle differences in tumour heterogeneity
between responders and non-responders. The
purpose of this study was to prospectively evaluate multi-parametric MRI, combining
diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE), and a 3D quantitative
histogram analysis for assessment of tumour heterogeneity
and response to CRT in rectal cancer.Methods
Thirty-nine patients
with locally advanced (Stage II – III) rectal cancer undergoing preoperative
CRT followed by surgery were enrolled on this study. MRI was performed at 3
time-points: pre-CRT, week 3 CRT, and post CRT (pre-surgery). The protocol
consisted of (i) T2W images, (ii) DWI using a
read-out segmented sequence (RESOLVE) with b-values 50 s/mm2, 800
s/mm2 and calculated 1400 s/mm2, 1&3 averages, and
ADC maps produced as part of protocol (iii) DCE with pre-contrast VIBE T1-weighted scans for T1 calculation followed by
injection of 0.1mM/kg gadolinium (Gadoversetamide) and 60 phases TWIST with a
5s temporal resolution. Butylscopolamine
20mg IV was administered prior to functional MRI sequences. CRT response was
defined according to modified Ryan et al set out in the AJCC Cancer Staging
Manual 7th Edition tumour regression grade (TRG). The entire original tumour site was
embedded for microscopic assessment. Two dedicated gastrointestinal
pathologists examined each case and reached consensus on TRG. TRG 0–1 were
classified as responders and TRG 2–3 as non-responders. Semi-automated
segmentation was used to define the entire hyperintense tumour on b-value
1400s/mm2 images. A voxel-by-voxel analysis of whole
tumour was used to produce histograms of ADC and Ktrans, and
combined scatterplots for each time-point. The ADC and Ktrans percentiles,
skewness and kurtosis by response status were assessed using two-sample
t-tests.Results
Of 39 patients, 6 had Stage II and 33 had Stage III
disease at diagnosis. Three
patients had pathologic complete response TRG 0 (7.7%), 12 had TRG 1 (30.8%),
14 had TRG 2 (35.9%), and 3 had TRG 3 (7.7%). One patient who refused
surgery had a clinical complete response (2.6%) on colonoscopy and biopsy at 18
months, and was classified as a responder.
Five patients with mucinous pathology (12.8%) and 1 patient (2.6%) who did
not have response status were excluded from analysis. The histograms showed skewness
of ADC was an approximately symmetric distribution that became more symmetric
over time. Ktrans had a highly skewed distribution at each
time-point that decreased from baseline to on-treatment, then remained stable. Of
the histogram quantiles tested, post-CRT ADC 75th (responders vs.
non-responders 1620x10-6 vs. 1547x10-6, p=0.036) and 90th
percentiles (responders vs. non-responders 1859x10-6 vs 1753x10-6,
p=0.019) were significant for predicting response. All Ktrans
quantiles were higher in non-responders than responders at all time-points however,
this was not significant (p>0.10). There was no bivariate pattern in change
over time on combined scatterplots of ADC and Ktrans by response
status.Discussion
Accurate prediction of response
would allow for appropriate selection of patients for a more conservative
surgical technique, or a wait-and-watch approach, thereby minimising or
avoiding surgical morbidity.1,2 This protocol allowed for 3D
characterization of diffusion (DWI) and perfusion (DCE) changes in tumour in
response to CRT. Histopathology analysis in this study was rigorous, with
entire tumour bed embedded for analysis and consensus readings by 2
gastrointestinal pathologists. In this study post-CRT ADC 75th and
90th percentiles were the best histogram parameters for the
prediction of CRT response. DCE-MRI Ktrans did not assist in the
prediction of CRT response, despite standardization of the DCE protocol in this
study. Rectal peristalsis was minimized by butylscopolamine, and rigid
pre-registration of flip angle to dynamic images, which had to be performed
outside of commercial software, was done to correct for patient motion and
ensure accurate voxel-wise analysis over 60 phases. An increase in Ktrans
during CRT was seen on DCE-MRI, indicating increased perfusion in response to
CRT. Post-CRT Ktrans was higher in non-responders than responders,
suggesting greater residual perfusion following CRT in non-responders, however
this was not significantly different by response status.Conclusion
Post-CRT
DWI ADC 75th and 90th quantiles were promising parameters
for prediction of CRT response in patients with locally advanced rectal cancer.
DCE-MRI and multiparametric scatterplots combining ADC and Ktrans
did not add value in predicting response.Acknowledgements
No acknowledgement found.References
1Pham et al. BJR 2017;90(1072).
2Maas et al. J Clin Oncol 2011;29(35):4633