Abstract
Purpose
3′-Deoxy-3′-18F-fluorothymidine (FLT) positron emission tomography (PET) has limited utility in abdominal imaging due to high physiological hepatic uptake of tracer. We evaluated FLT PET/CT combined with a temporal-intensity information-based voxel-clustering approach termed kinetic spatial filtering (FLT PET/CTKSF) for early prediction of response and survival outcomes in locally advanced and metastatic pancreatic cancer patients receiving gemcitabine-based chemotherapy.
Methods
Dynamic FLT PET/CT data were collected before and 3 weeks after the first cycle of chemotherapy. Changes in tumour FLT PET/CT variables were determined. The primary end point was RECIST 1.1 response on contrast-enhanced CT after 3 months of therapy.
Results
Twenty patients were included. Visual distinction between tumours and normal pancreas was seen in FLT PETKSF images. All target lesions (>2 cm), including all primary pancreatic tumours, were visualised. Of the 11 liver metastases, 3 (<2 cm) were not visible after kinetic filtering. Of the 20 patients, 7 progressed (35 %). Maximum standardised uptake value at 60 min post-injection (SUV60,max) significantly increased in patients with disease progression (p = 0.04). Receiver-operating characteristic curve analysis indicated that a threshold of SUV60,max increase of ≥ 12 % resulted in sensitivity, specificity and positive predictive value (PPV) of 71, 100 and 100 %, respectively [area under the curve (AUC) 0.90, p = 0.0001], to predict patients with disease progression. Changes in SUV60,max were not predictive of survival.
Conclusion
FLT PET/CT detected changes in proliferation, with early increase in SUV60,max predicting progressive disease with a high specificity and PPV. Therefore, FLT PET/CT could be used as an early response biomarker for gemcitabine-based chemotherapy, to select a poor prognostic group who may benefit from novel therapeutic agents in advanced and metastatic pancreatic cancer.
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Acknowledgments
The authors would like to thank Ms. Kozlowski for patient recruitment and editorial assistance and Dr. Petrides for reviewing the NUTH scans for incidental findings. We also thank the radiographers, radiochemists, blood lab staff and finally all the patients who have taken part in this study.
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Funding
This study was supported by UK Medical Research Council (MRC) grant MC-A652-5PY80, Joint Cancer Research-UK (CRUK) and Engineering and Physical Sciences Research Council Cancer Imaging Centre, Imperial College London (ICL), in association with MRC and Department of Health grant C2536/A10337, Experimental Cancer Medicine Centres' grant C37/A7283 and National Institute for Health Research Biomedical Research Centre award to Imperial College Healthcare NHS Trust and ICL. In Newcastle it was supported by CRUK Award C29821/A10348.
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Ethical approval
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Statement on welfare of animals
This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in this study.
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Amarnath Challapalli and Tara Barwick contributed equally to this work and are joint first authors.
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Online Resource 1
Performance of KSF in patients scanned at ICHNT and NUTH (a, b) and decay-corrected time-activity curves, normalised by injected activity (tissue activity) of the three liver metastases not visualised on KSF (c). Data are average tissue activity values and error bars represent one SD. Average reduction in SUV in the primary tumours (a) was 18 % and in the liver metastases (b) was 28 %. (GIF 27 kb)
Online Resource 2
Voxel representations depicting tumour heterogeneity, in pancreatic tumours (a, b) and liver metastases (c, d) in a tumours of size < 30 mm (homogeneous tumour on filtered images) and in a tumour of size > 55 mm (heterogeneous tumour on filtered images). The dotted line on the X-axis corresponds to SUV of 2. Note different scales of Y-axis. (GIF 34 kb)
Online Resource 3
Changes in voxel intensities with therapy, in pancreatic tumour (a, b) and liver metastases (c, d) in an NP and P, respectively. The dotted line on the X-axis corresponds to SUV 2. Note different scales of Y-axis. (GIF 38 kb)
Online Resource 4
Waterfall plots (a) and box and whisker plots (b) of summed lesions for measures of HiVox showing some degree of reduction in the HiVox, but no significant changes in the HiVox between NP and P on group analysis of the data. (GIF 18 kb)
Online Resource 5
Changes in imaging variables, application of KSF and influence of single agent gemcitabine or combination chemotherapy. There was no difference in response with single agent vs combination chemotherapy. NP non-progressors (patients with PR or SD), P progressors. (GIF 44 kb)
Online Resource 6
Group analysis of the imaging data showing the difference between baseline and post-treatment histogram parameters in the summed lesions in non-progressors (NP) and progressors (P): box and whisker plots for the measures of median (a), mode (b), skewness (c), kurtosis (d), 10th (e), 90th (f), 50th (g) and 75th (h) percentiles . Note different scales of Y-axis. (GIF 47 kb)
Online Resource 7
Group analysis of imaging data showing the difference between baseline and post-treatment FLT uptake in the summed lesions in non-progressors (NP) and progressors (P): box and whisker plots for the measures of a SUV60,ave and b SUV60,max. Note different scales of Y-axis. * denotes p < 0.05 (GIF 40 kb)
Online Resource 8
Expression of hENT1 (a) and Ki-67 (b) in pancreatic cancer by immunohistochemistry. Representative section of a case of pancreatic cancer showing high expression of hENT1 with a diffuse cytoplasmic and nuclear pattern is seen in a. A representative case showing moderate expression of Ki-67 nuclear expression in pancreatic cancer is shown in b. Magnification ×400. (PPT 229 kb)
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Challapalli, A., Barwick, T., Pearson, R.A. et al. 3′-Deoxy-3′-18F-fluorothymidine positron emission tomography as an early predictor of disease progression in patients with advanced and metastatic pancreatic cancer. Eur J Nucl Med Mol Imaging 42, 831–840 (2015). https://doi.org/10.1007/s00259-015-3000-2
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DOI: https://doi.org/10.1007/s00259-015-3000-2