Skip to main content

Advertisement

SpringerLink
Log in

3′-Deoxy-3′-18F-fluorothymidine positron emission tomography as an early predictor of disease progression in patients with advanced and metastatic pancreatic cancer

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. doi:10.3322/caac.20138.

    Article  PubMed  Google Scholar 

  2. Cartwright T, Richards DA, Boehm KA. Cancer of the pancreas: are we making progress? A review of studies in the US Oncology Research Network. Cancer Control 2008;15:308–13.

    PubMed  Google Scholar 

  3. Sultana A, Smith CT, Cunningham D, Starling N, Neoptolemos JP, Ghaneh P. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol 2007;25:2607–15. doi:10.1200/JCO.2006.09.2551.

    Article  PubMed  Google Scholar 

  4. Ciliberto D, Botta C, Correale P, Rossi M, Caraglia M, Tassone P, et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2013;49:593–603. doi:10.1016/j.ejca.2012.08.019.

    Article  CAS  PubMed  Google Scholar 

  5. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. doi:10.1016/j.ejca.2008.10.026.

    Article  CAS  PubMed  Google Scholar 

  6. Costello E, Greenhalf W, Neoptolemos JP. New biomarkers and targets in pancreatic cancer and their application to treatment. Nat Rev Gastroenterol Hepatol 2012;9:435–44. doi:10.1038/nrgastro.2012.119.

    Article  CAS  PubMed  Google Scholar 

  7. Zhu A, Lee D, Shim H. Metabolic positron emission tomography imaging in cancer detection and therapy response. Semin Oncol 2011;38:55–69. doi:10.1053/j.seminoncol.2010.11.012.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Choi M, Heilbrun LK, Venkatramanamoorthy R, Lawhorn-Crews JM, Zalupski MM, Shields AF. Using 18F-fluorodeoxyglucose positron emission tomography to monitor clinical outcomes in patients treated with neoadjuvant chemo-radiotherapy for locally advanced pancreatic cancer. Am J Clin Oncol 2010;33:257–61. doi:10.1097/COC.0b013e3181a76a0b.

    PubMed  Google Scholar 

  9. Kuwatani M, Kawakami H, Eto K, Haba S, Shiga T, Tamaki N, et al. Modalities for evaluating chemotherapeutic efficacy and survival time in patients with advanced pancreatic cancer: comparison between FDG-PET, CT, and serum tumor markers. Intern Med 2009;48:867–75.

    Article  PubMed  Google Scholar 

  10. Rose DM, Delbeke D, Beauchamp RD, Chapman WC, Sandler MP, Sharp KW, et al. 18Fluorodeoxyglucose-positron emission tomography in the management of patients with suspected pancreatic cancer. Ann Surg 1999;229:729–37. discussion 37–8.

  11. Bang S, Chung HW, Park SW, Chung JB, Yun M, Lee JD, et al. The clinical usefulness of 18-fluorodeoxyglucose positron emission tomography in the differential diagnosis, staging, and response evaluation after concurrent chemoradiotherapy for pancreatic cancer. J Clin Gastroenterol 2006;40:923–9. doi:10.1097/01.mcg.0000225672.68852.05.

    Article  PubMed  Google Scholar 

  12. Buck AC, Schirrmeister HH, Guhlmann CA, Diederichs CG, Shen C, Buchmann I, et al. Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis: does in vivo FDG uptake correlate with proliferative activity? J Nucl Med 2001;42:721–5.

    CAS  PubMed  Google Scholar 

  13. Higashi T, Saga T, Nakamoto Y, Ishimori T, Fujimoto K, Doi R, et al. Diagnosis of pancreatic cancer using fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET)–usefulness and limitations in "clinical reality". Ann Nucl Med 2003;17:261–79.

    Article  PubMed  Google Scholar 

  14. Klein WM, Hruban RH, Klein-Szanto AJ, Wilentz RE. Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod Pathol 2002;15:441–7. doi:10.1038/modpathol.3880544.

    Article  PubMed  Google Scholar 

  15. van Waarde A, Cobben DC, Suurmeijer AJ, Maas B, Vaalburg W, de Vries EF, et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med 2004;45:695–700.

    PubMed  Google Scholar 

  16. Barwick T, Bencherif B, Mountz JM, Avril N. Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation. Nucl Med Commun 2009;30:908–17. doi:10.1097/MNM.0b013e32832ee93b.

    Article  CAS  PubMed  Google Scholar 

  17. Quon A, Chang ST, Chin F, Kamaya A, Dick DW, Loo Jr BW, et al. Initial evaluation of 18F-fluorothymidine (FLT) PET/CT scanning for primary pancreatic cancer. Eur J Nucl Med Mol Imaging 2008;35:527–31. doi:10.1007/s00259-007-0630-z.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Herrmann K, Eckel F, Schmidt S, Scheidhauer K, Krause BJ, Kleeff J, et al. In vivo characterization of proliferation for discriminating cancer from pancreatic pseudotumors. J Nucl Med 2008;49:1437–44. doi:10.2967/jnumed.108.052027.

    Article  CAS  PubMed  Google Scholar 

  19. Herrmann K, Erkan M, Dobritz M, Schuster T, Siveke JT, Beer AJ, et al. Comparison of 3'-deoxy-3'-[(18)F]fluorothymidine positron emission tomography (FLT PET) and FDG PET/CT for the detection and characterization of pancreatic tumours. Eur J Nucl Med Mol Imaging 2012;39:846–51. doi:10.1007/s00259-012-2061-8.

    Article  CAS  PubMed  Google Scholar 

  20. Shields AF, Grierson JR, Muzik O, Stayanoff JC, Lawhorn-Crews JM, Obradovich JE, et al. Kinetics of 3'-deoxy-3'-[F-18]fluorothymidine uptake and retention in dogs. Mol Imaging Biol 2002;4:83–9.

    Article  PubMed  Google Scholar 

  21. Zasadny KR, Wahl RL. Enhanced FDG-PET tumor imaging with correlation-coefficient filtered influx-constant images. J Nucl Med 1996;37:371–4.

    CAS  PubMed  Google Scholar 

  22. Contractor K, Challapalli A, Tomasi G, Rosso L, Wasan H, Stebbing J, et al. Imaging of cellular proliferation in liver metastasis by [18F]fluorothymidine positron emission tomography: effect of therapy. Phys Med Biol 2012;57:3419–33. doi:10.1088/0031-9155/57/11/3419.

    Article  CAS  PubMed  Google Scholar 

  23. Gray KR, Contractor KB, Kenny LM, Al-Nahhas A, Shousha S, Stebbing J, et al. Kinetic filtering of [(18)F]Fluorothymidine in positron emission tomography studies. Phys Med Biol 2010;55:695–709. doi:10.1088/0031-9155/55/3/010.

    Article  CAS  PubMed  Google Scholar 

  24. Cleij MC, Steel CJ, Brady F, Ell PJ, Pike VW, Luthra SK. An improved synthesis of 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) and the fate of the precursor 2,3′-anhydro-5′-O-(4,4′-dimethoxytrityl)-thymidine. J Label Compd Radiopharm 2001;44:S871–3.

    Article  Google Scholar 

  25. Contractor KB, Kenny LM, Stebbing J, Rosso L, Ahmad R, Jacob J, et al. [18F]-3'Deoxy-3'-fluorothymidine positron emission tomography and breast cancer response to docetaxel. Clin Cancer Res 2011;17:7664–72. doi:10.1158/1078-0432.CCR-11-0783.

    Article  CAS  PubMed  Google Scholar 

  26. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009;50 Suppl 1:122S–50S. doi:10.2967/jnumed.108.057307.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. de Langen AJ, Klabbers B, Lubberink M, Boellaard R, Spreeuwenberg MD, Slotman BJ, et al. Reproducibility of quantitative 18F-3'-deoxy-3'-fluorothymidine measurements using positron emission tomography. Eur J Nucl Med Mol Imaging 2009;36:389–95. doi:10.1007/s00259-008-0960-5.

    Article  PubMed  Google Scholar 

  28. Kenny L, Coombes RC, Vigushin DM, Al-Nahhas A, Shousha S, Aboagye EO. Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging 2007;34:1339–47. doi:10.1007/s00259-007-0379-4.

    Article  PubMed  Google Scholar 

  29. Tehrani OS, Shields AF. PET imaging of proliferation with pyrimidines. J Nucl Med 2013;54:903–12. doi:10.2967/jnumed.112.112201.

    Article  CAS  PubMed  Google Scholar 

  30. Weber WA. Monitoring tumor response to therapy with 18F-FLT PET. J Nucl Med 2010;51:841–4. doi:10.2967/jnumed.109.071217.

    Article  PubMed  Google Scholar 

  31. Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 2009;136:187–95. doi:10.1053/j.gastro.2008.09.067.

    Article  PubMed  Google Scholar 

  32. Paproski RJ, Young JD, Cass CE. Predicting gemcitabine transport and toxicity in human pancreatic cancer cell lines with the positron emission tomography tracer 3'-deoxy-3'-fluorothymidine. Biochem Pharmacol 2010;79:587–95. doi:10.1016/j.bcp.2009.09.025.

    Article  CAS  PubMed  Google Scholar 

  33. Dittmann H, Dohmen BM, Kehlbach R, Bartusek G, Pritzkow M, Sarbia M, et al. Early changes in [18F]FLT uptake after chemotherapy: an experimental study. Eur J Nucl Med Mol Imaging 2002;29:1462–9. doi:10.1007/s00259-002-0925-z.

    Article  CAS  PubMed  Google Scholar 

  34. Contractor KB, Kenny LM, Stebbing J, Challapalli A, Al-Nahhas A, Palmieri C, et al. Biological basis of [11C]choline-positron emission tomography in patients with breast cancer: comparison with [18F]fluorothymidine positron emission tomography. Nucl Med Commun 2011;32:997–1004. doi:10.1097/MNM.0b013e328349567b.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Compliance with ethical standards

ᅟ

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.

Conflicts of interest

None.

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.

Author information

Author notes

    Authors and Affiliations

    1. Department of Surgery & Cancer, Imperial College London (ICL), London, UK

      Amarnath Challapalli, Tara Barwick, Shairoz Merchant & Eric O. Aboagye

    2. Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

      Rachel A. Pearson, Elizabeth C. Howell & Ross J. Maxwell

    3. Department of Pathology, Imperial College Healthcare NHS Trust, London, UK

      Francesco Mauri

    4. Northern Centre for Cancer Care, Newcastle Upon Tyne Hospitals NHS Foundation Trust, London, UK

      Katherine Sumpter

    5. Department of Investigative Medicine, ICL, London, UK

      Rohini Sharma

    6. Department of Surgery & Cancer, ICL, Hammersmith Hospital, Du Cane Road, London, W120NN, UK

      Eric O. Aboagye

    Authors
    1. Amarnath Challapalli
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Tara Barwick
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Rachel A. Pearson
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Shairoz Merchant
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Francesco Mauri
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Elizabeth C. Howell
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Katherine Sumpter
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Ross J. Maxwell
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Eric O. Aboagye
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Rohini Sharma
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Eric O. Aboagye.

    Additional information

    Amarnath Challapalli and Tara Barwick contributed equally to this work and are joint first authors.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    High resolution image (TIFF 916 kb)

    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)

    High resolution image (TIFF 996 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)

    High resolution image (TIFF 1039 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)

    High resolution image (TIFF 617 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)

    High resolution image (TIFF 1357 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)

    High resolution image (TIFF 1870 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)

    High resolution image (TIFF 963 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)

    ESM 9

    (DOCX 27 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    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

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00259-015-3000-2

    Keywords

    Search

    Navigation